Sen. Robert Menendez entered a fresh “not guilty” plea in his corruption trial Tuesday as jury selection got underway in New Jersey in what is shaping up as an embarrassing show for national Democrats.

As Mr. Menendez’s colleagues return to Washington on Sept. 6 from a long summer vacation, the three-term senator will be staring down prosecutors who accuse him of taking gifts and trips from a wealthy donor, in exchange for political favors.

The trial could last months, and a conviction could send shock waves through New Jersey and Washington, forcing appointment of a midstream replacement.

“Obviously we’re all waiting to see what happens with the outcome,” Sen. Ben Cardin, Maryland Democrat, said on MSNBC’s “Morning Joe” program Tuesday. “This has been going on now for two and a half years. So I think we’re all pleased to see that hopefully this will come to an end.”

The new “not guilty” plea came during closed proceedings, The Associated Press reported, calling it an unusual move for the judge to close the courtroom.

“Looking forward to picking a good jury,” the senator told CBS2 in New York as he walked into the courtroom earlier.

Mr. Menendez was accused in April 2015 of accepting close to $1 million in campaign contributions and gifts from co-defendant Dr. Salomon Melgen in exchange for political favors. The largesse included trips to the Dominican Republic, a Paris vacation and golf rounds.

Prosecutors have said Mr. Menendez advocated on behalf of Melgen in a Medicare billing dispute totaling nearly $9 million, and that he also helped several of the doctor’s girlfriends get visas.

Melgen, convicted in April on multiple counts in a separate case tied to Medicare fraud, also pleaded not guilty Tuesday to charges from an updated indictment handed up last fall. U.S. District Judge William Walls had previously dismissed two bribery counts against each defendant.

Lawyers for the defendants have said the gifts and contributions were tied to friendship and did not constitute an attempt to win political favors, and that the broader indictment could jeopardize relatively routine interactions between politicians and their supporters.

More recently, lawyers cited the 2016 U.S. Supreme Court decision overturning the convictions on similar corruption charges of former Virginia Gov. Bob McDonnell, arguing that the McDonnell case narrowed what could be constituted as bribery in federal statutes.

In July, a federal appeals court also cited the 2016 McDonnell decision in overturning corruption convictions for former New York state Assembly Speaker Sheldon Silver.

Perhaps hedging their bets, prosecutors have also charged Mr. Menendez with making false statements on financial disclosure forms by omitting Melgen’s gifts.

That charge could stick no matter what happens with the corruption case.

The implications of the trial and a potential conviction are tremendous for Mr. Menendez personally, as well as for related ripple effects on the makeup of the U.S. Senate, where Republicans currently hold an effective 52-48 majority.

After the April 2015 indictment, Mr. Menendez gave up his position as the top-ranking Democrat on the Senate Foreign Relations Committee to Mr. Cardin.

In that post, he had been critical of former President Barack Obama’s recent diplomatic overtures to Cuba, as well as the outlines of the former administration’s deal with Iran over the country’s nuclear program.

If he is convicted and steps down before New Jersey Gov. Chris Christie leaves office in January, Mr. Christie, a Republican, would pick a successor to serve until the seat is up for re-election in November 2018.

If he doesn’t step down, it would take two-thirds of the Senate to expel Mr. Menendez, meaning at least 15 Democrats would have to join Republicans to boot him out if the GOP vote is unanimous.

Democrats have generally been tight-lipped about the criminal case as it’s worked its way through court proceedings over the last 2½ years or so.

The Senate Democrats’ campaign arm did not respond to questions Tuesday about the case, including whether Mr. Menendez would continue to receive support if he is ultimately convicted and chooses to seek re-election.

• This report is based in part on wire service dispatches.

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