Joe Biden is projected to win Alabama, Tennessee, North Carolina and Virginia as 14 states vote to pick a Democratic White House candidate on Super Tuesday.
Bernie Sanders is expected to win Colorado and Vermont, but Elizabeth Warren is in trouble in Massachusetts.
Mr Biden, a moderate Democrat, and Mr Sanders, a left-winger, offer starkly different visions for America’s future.
They lead the race to anoint a Democrat who will face President Donald Trump, a Republican, in November’s election.
Buoyed by last-minute endorsements from former rivals who dropped out of the race, Mr Biden is hoping to blunt the momentum of Mr Sanders, who was the frontrunner nationally on the eve of the vote.
Mr Biden’s under-staffed and under-funded campaign has been resurgent since his commanding win in South Carolina’s primary at the weekend. It was the first time the 77-year-old had won any contest in three White House runs.
Exit poll data suggests black voters, a crucial bloc for the Democratic party, have been key to the former US vice-president’s projected victories in Virginia and North Carolina.
Mr Sanders, a 78-year-old independent senator who is planning to transform the American economy with a multi-trillion dollar, higher taxation blueprint on everything from healthcare to education, had been expected to win his largely white, rural home state of Vermont.
Also appearing on a presidential ballot for the first time after skipping all four contests last month is Michael Bloomberg.
The former New York mayor, who has spent half a billion dollars of his own money, will win the US territory of American Samoa, according to US media.
Mr Biden aims to consolidate the centrist Democratic vote by barging aside Mr Bloomberg, one of the world’s richest men.
But the billionaire has lowered expectations for his performance on Tuesday, indicating he plans to fight for the presidential nomination all the way to the party convention in Milwaukee, Wisconsin, in July.
In a bad sign for Senator Warren, exit polls from her home state of Massachusetts indicate she is in a tight race against Mr Sanders and Mr Biden.
Texas, Maine, Minnesota and Arkansas are currently toss-ups between Mr Sanders and Mr Biden.
CBS News projects Mr Biden has the edge in Oklahoma.
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Super Tuesday offers an electoral bonanza of 1,344 of the 1,991 delegates needed to clinch the Democratic White House nomination under America’s quirky political system.
Amy Klobuchar and Pete Buttigieg, who were competing with Mr Biden for centrist Democrats, ended their campaigns this week and endorsed the former vice-president under Barack Obama.
The Sanders team have said the abrupt exit by Ms Klobuchar and Mr Buttigieg is part of an all-out mobilisation by the party establishment and big money donors to freeze out the Vermont senator.
The Democratic party is at a crossroads as its voters decide which candidate has the best chance of denying Mr Trump a second term in office this autumn.
Mr Biden presents himself as an electable pragmatist who can bring incremental change, whereas Mr Sanders has promised a revolution.
Mr Sanders’ detractors say he is too much of a radical firebrand to win over the swing voters needed to win the White House.
Mr Biden’s critics say his campaign is uninspiring, and he brings too much political baggage from his lifelong career as a Washington insider.
Mr Trump, meanwhile, could not resist taking a dig at Mr Bloomberg.
The president tweeted a video of his rival New York billionaire eating a donut, commenting: “Mini Mike, don’t lick your dirty fingers. Both unsanitary and dangerous to others and yourself!”