Oscar-winning director Jonathan Demme died Wednesday in New York of cancer complications, his publicist told Variety. He was 73 years old.

Demme is best known for directing “The Silence of the Lambs,” the 1991 horror-thriller that was a box office smash, a critical triumph, and introduced moviegoers to Anthony Hopkins’ Hannibal Lecter, a charismatic serial with a yen for chianti, fava beans, and cannibalism. The story of a novice FBI analyst (Jodie Foster) on the trail of a murderer became only the third film in history to win Academy Awards in all the top five categories ( picture, actor, actress, director, and adapted screenplay), joining the ranks of “It Happened One Night” and “One Flew Over the Cuckoo’s Nest.”

Though he had his greatest success terrifying audiences, most of Demme’s work was looser and quirkier. In particular, he showed a great humanism and an empathy for outsiders in the likes of “Melvin and Howard,” the story of a service station owner who claimed to have been a beneficiary of Howard Hughes, and “Something Wild,” a screwball comedy about a banker whose life is turned upside down by a kooky woman. He also scored with “Married to the Mob” and oversaw “Stop Making Sense,” a documentary about the Talking Heads that is considered to be a seminal concert film.

Following “The Silence of the Lambs,” Demme used his clout to make “Philadelphia,” one of the first major studio films to tackle the AIDS crisis and a movie that won Tom Hanks his first Oscar for playing a gay lawyer.

The director most recently worked on an episode of the Fox police drama “Shots Fired,” which is scheduled to air on April 26 — the same day Demme’s death was announced. He also filmed the 2016 concert film “Justin Timberlake + the Tennessee Kids.” His most recent narrative feature was 2015’s “Ricki and the Flash,” starring Meryl Streep as an aging rocker who must return home to Indiana due to a family crisis. The film disappointed at the box office and reviews were muted.

After jumping on the CB radio craze with the under-appreciated indie “Handle With Care,” Demme came to the attention of Hollywood with the 1980 film “Melvin and Howard.” Both films starred Paul LeMat; Jason Robards co-starred as a bearded, bedraggled Hughes encountered by struggling Melvin Dumont, who helps Howard out — only to be left $156 million in a Hughes will of dubious authenticity. The film worked because it was not about Hughes but about Dumont, played by Paul Le Mat (one of Demme’s favorite actors). It drew three Oscar nominations, winning for best supporting actress (Mary Steenburgen) and original screenplay (Bo Goldman), while Robards also drew a nomination.

The 1984 film “Swing Shift,” a romantic dramedy set on the homefront during WWII and starring Goldie Hawn and Kurt Russell, was directed by Demme but taken out of his hands by the studio and recut, reportedly to make Hawn’s characterization more flattering. Director and star clashed during the production with Hawn wanting a more conventional love story with laughs and Demme preferring something with rougher edges.

Two years later, Demme rebounded with the New Wave-flavored indie comedy “Something Wild.” He drew an erotically anarchical performance from Melanie Griffith, as a brunette on the run, and coaxed an impressive debut from Ray Liotta as Griffith’s lunatic ex-boyfriend.

Demme had a way with actors, discovering new talent and allowing performers to stretch their muscles. His 1988 comedy “Married to the Mob,” starred Michelle Pfeiffer, replete with loud hair and a thick New York accent, in a performance that showed the actress’ range. It also benefited from excellent supporting performances by Dean Stockwell as the Mafia boss and Mercedes Ruehl as his far fiercer wife. Stockwell earned an Oscar nomination.

In addition to “Stop Making Sense,” Demme did documentaries on the Pretenders, Bruce Springsteen and Neil Young, and he also directed quite a number of music videos, drawing a Grammy nomination in 1987 for best long form music video for “Sun City: Artists United Against Apartheid.”

Demme’s nonfiction work also dipped into politics and social issues, profiling the likes of Jimmy Carter and Nelson Mandela. He made two documentaries about Haiti, 1988’s “Haiti Dreams of Democracy” and 2003’s critically acclaimed “The Agronomist.” Of the latter the New York Times said, “The turbulence that led to the removal of Jean-Bertrand Aristide from Haiti’s presidency gives ‘The Agronomist,’ a superb new documentary by Jonathan Demme, a melancholy timeliness. Its hero, Jean Dominique, embodies the fragile, perpetual hope that Haiti might someday nurture a just and decent political order.”

Demme’s commercial prowess waned in the late 1990s and early aughts. “Beloved,” a 1998 adaptation of Toni Morrison’s award-winning book, received some critical support, but was a massive bomb and failed to attract much Oscar attention. Then there was an ill-advised 2002 “Charade” remake “The Truth About Charlie,” which starred Mark Wahlberg and Thandie Newton and proved a disservice to the classic Stanley Donen original.

He also failed to convince critics that his 2004’s big-budget, high-profile remake of “The Manchurian Candidate” needed to be made. The film starred Denzel Washington, Liev Schreiber and Meryl Streep, which hit in the middle of a contentious presidential election between George W. Bush and John Kerry, but despite the political climate, it didn’t make much of a splash.

The 2008 film “Rachel Getting Married,” was a return to form for Demme, and served as an excellent vehicle for Anne Hathaway to demonstrate acting ability in a largely unsympathetic role of a young woman, out of rehab long enough to attend the wedding of the sister. Hathaway received her first Oscar nomination for the part.

Demme directed an adaptation of the Ibsen play “The Master Builder,” penned by and starring Wallace Shawn, in 2013. In 2015, in addition to “Ricki and the Flash,” he directed the docu-series “The New Yorker Presents,” bringing to life the iconic magazine.

Robert Jonathan Demme was born in Baldwin, Long Island, New York, and attended the University of Florida. Like John Sayles, he began his directing career in Roger Corman’s stable, helming women’s prison exploitation film “Caged Heat” in 1974; nostalgic road trip film “Crazy Mama,” starring Cloris Leachman, in 1975; and Peter Fonda action film “Fighting Mad” in 1976.

In 2006 Demme was presented with the National Board of Review’s Billy Wilder Award. Demme’s nephew, director Ted Demme, died in 2002 at age 38.

Demme was previously married to director-producer Evelyn Purcell. He is survived by second wife Joanne Howard and their three children: Ramona, Brooklyn and Jos.