Reilly Opelka smashes an ace to complete the upset win over No. 9 John Isner. (0:18)

MELBOURNE, Australia -- John Isner hit more aces than his opponent: 47-40. He delivered more total winners and finished with more overall points, too. What Isner failed to do for the first time in his career was beat an American foe at a Grand Slam tournament, and now the highest-ranked man from the U.S. is gone from the Australian Open.

Reilly Opelka, ranked just 97th, earned his first victory in a main-draw match at a major by edging Isner in four tiebreakers 7-6 (4), 7-6 (6), 6-7 (4), 7-6 (5) on Monday in the first round at Melbourne Park.

Isner, 33, seeded No. 9 and a semifinalist at Wimbledon last year, had been 9-0 in all-U.S. contests at the Slams.

If anyone is his equal when it comes to big serves, though, it's Opelka, 21, who at 6-foot-11 is an inch taller than Isner.

Isner went up a break in the fourth set and served to force a fifth while ahead 5-4. But he was broken there, missing one backhand followed by a trio of forehands. Opelka took the eventual tiebreaker with the help of three aces, including one at 141 mph to close out the match.

Defending champion Roger Federer began his quest for a record seventh Australian Open title with a 6-3, 6-4, 6-4 win over Denis Istomin.

Playing before a capacity crowd of more than 15,000 at Rod Laver Arena, Federer broke Istomin's serve at 2-2 in the third set on the way to his seventh win in a row against the Uzbekistan player.

Federer's seventh Australian Open title would be the most by any player. Novak Djokovic (who plays his first-round match on Tuesday) and Roy Emerson also have six wins each at the Australian Open, although Emerson's wins were before the start of the Open era in 1968.

A win in Melbourne would also be Federer's 100th tour-level title, the second man after Jimmy Connors to win 100 titles. Connors had 109.

No. 2-seeded Rafael Nadal had little trouble despite missing a lot of tennis since September.

Nadal moved on with a 6-4, 6-3, 7-5 win over Australian wild-card entry James Duckworth, his first match back at Rod Laver Arena since he had to retire in his quarterfinal match in the tournament last year.

The 17-time major winner hadn't played since retiring from his semifinal at the US Open because of a knee injury, and then had surgery on his right ankle in November. He withdrew from a warm-up tournament in Brisbane in the first week of the season because of a muscle strain in his thigh.

"Not easy to come back after a lot of months of [no] competition, especially against a player playing super-aggressive every shot," Nadal said. "It's very difficult to start after an injury -- I know it very well. It's very special to be back."

Nadal showed no signs of any issues against Duckworth. His only hiccup came when he served for the match in the ninth game of the third set and was broken at love. He returned the favor quickly, though, to seal his spot in the second round.

Nadal has lost only twice in the first round at Grand Slams -- to Steve Darcis at 2013 Wimbledon and to Fernando Verdasco here in 2016 -- and is aiming to be the first man in the Open era to win all four majors at least twice.

Tomas Berdych picked up a surprisingly easy victory over the 13th-seeded Kyle Edmund, a 2018 semifinalist here, beating him 6-3, 6-0, 7-5.

Edmund made 36 unforced errors, 22 more than Berdych. Edmund also managed to earn only one break point and failed to convert it, while Berdych broke him five times.

Berdych was the 2010 runner-up at Wimbledon and has twice been a semifinalist at the Australian Open. Edmund's top result at a major came a year ago in Melbourne.

Fifth-seeded Kevin Anderson won his first match at Melbourne Park since 2015 when he beat Adrian Mannarino 6-3, 5-7, 6-2, 6-1. Also advancing on the men's side were No. 19 Nikoloz Basilashvili and No. 26 Fernando Verdasco.

Bernard Tomic was beaten 6-2, 6-4, 7-6 (3) by sixth-seeded Marin Cilic, then continued his criticism of Australia's Davis Cup captain, saying Lleyton Hewitt is causing division among the players and should be replaced.

Tomic said he would not play Davis Cup again with Hewitt as captain.

"No one likes him anymore,'' Tomic said of Hewitt. "We have a lot of issues that not a lot of players are happy about ... he's doing the wrong thing and everyone's leaving.''

Tomic played Davis Cup for 10 years but hasn't played consistently since Hewitt has been in charge of the team.

The Associated Press contributed to this report.