Elizabeth Warren took Bernie Sanders head-on over his alleged comment that a woman could not beat Donald Trump, saying she had never lost an election, unlike the men on the debate stage.
In the final televised debate before voting begins in the race for the Democratic nomination, Ms Warren leaned into a row with fellow left-winger Mr Sanders about a comment he is reported to have made in a private meeting between the pair in December 2018.
Video footage also appeared to show Ms Warren declining to shake hands with Mr Sanders as they exchanged words after the debate.
The dispute brought to the fore the concerns among some Democratic voters that sexism played a role in Mr Trump's victory over Hillary Clinton in 2016.
Asked about the claims during Tuesday night's debate, Mr Sanders strongly rebuked the claims saying: "I didn’t say it... Does anybody in their right mind think a woman can't be elected president? Of course a woman can win."
The Vermont senator went on to say it was “incomprehensible” he would make such a comment. Ms Warren, who represents Massachusetts in the Senate, stood behind her accusation and used the opportunity to make a forceful case for a female president.
"Bernie is my friend, and I am not here to try to fight with Bernie," she told the audience in Des Moines, Iowa. "But look, this question about whether or not a woman can be president has been raised, and it’s time for us to attack it head on."
Ms Warren used the moment to turn the heat on the four male candidates on the stage, saying "collectively they have lost 10 elections", while herself and the only other female on stage, Amy Klobuchar, had won every race they had run in.
There was also a brief skirmish between Mr Sanders, who opposed the Iraq War, and Joe Biden, the former US vice president, who apologised for supporting for a 2002 measure authorising the military action.
Several candidates condemned Mr Trump's recent move to kill Iran's top general and his decision to keep US troops in the region. Others, including Pete Buttigieg, Mr Biden and Ms Klobuchar, said they supported maintaining a small military presence in the Middle East.
The terse exchange between Ms Warren and Mr Sanders, the two progressive candidates in the race, brought a week of growing tensions between the pair to a head.
The longtime friends had avoided directly sparring with each other since entering the race, choosing instead to target the party's moderate wing, and in particular the front runner Mr Biden.
However at the start of the week it emerged Mr Sanders' campaign had a script for cold calls where his volunteers were urged to tell voters Ms Warren was being backed by the elite if her candidacy was mentioned.
Shortly afterwards Mr Sanders’s alleged comment about a woman not being able to beat Mr Trump surfaced, leading to speculation it was briefed by the Warren campaign.
The dispute deepened on Monday when Ms Warren took the unusual step of confirming the report, even as Mr Sanders continued to deny it.
Voting begins in Iowa, the first state to make its decision on the nominee, in less than three weeks and Mr Sanders and Ms Warren are locked in second and third place in nationwide polling. Mr Biden is first.
Ms Warren saw an early surge in support and briefly overtook Mr Biden in October, but Mr Sanders has consistently led the field when it comes to generating campaign funding, taking in $34.5 million in the last quarter and topped a poll in Iowa this week.
David Axelrod, a former campaign strategist to President Barack Obama, praised Ms Warren's performance on the debate stage, telling CNN the 70-year-old had thrown "a grenade" into the Bernie Sanders campaign.
Meanwhile Mr Trump, who was holding a rally in Wisconsin, waded into the row, saying: "I don't believe that Bernie said that, I really don't. It's not the kind of thing Bernie would say."