The once-safe Democratic seat, held by party giant Edward Kennedy until his death in August 2009, is up for grabs in a tight race between Republican state Senator Scott Brown and Democrat state Attorney-General Martha Coakley.
Here are some reasons why the New England state's 6.5 million people might be turning away from Democrats:
National anti-incumbent sentiment
The party in power traditionally loses seats in an off-year election after a presidential victory, and for President Barack Obama the backlash seems well under way.
Massachusetts is traditionally among the most liberal U.S. states, but has become part of a national swing against Obama and the Democrats now in control of Congress.
Conservative groups have sent in millions of dollars in donations to fund advertising, and a small army of volunteers to help Brown get out the vote.
Even if Coakley squeaks out a win, the shift against the Democratic Party will be a rallying point for conservatives.
Healthcare legislation and costs
Concerns about cost of the potential healthcare legislation, as well as the rising federal deficit, have energized support for Brown.
The clearest policy difference between the two is Brown's vow to be the 41st vote against the Democrats' healthcare reform bill, and Coakley's vow to support the bill.
Respondents to several opinion polls cited healthcare reform, the weak economy and high unemployment as the biggest factors guiding their votes.
Massachusetts enacted a near-universal state healthcare law in 2006. The state arguably has less to gain from the federal measures now being considered.
Democrat is weak candidate
Democratic contender Coakley has had solid approval ratings as state attorney-general since 2006.
But after cruising to victory in a four-way primary battle in December, Coakley has run what many pundits have called an ineffective campaign -- especially compared with Brown, a personable attorney and former model.
Independent voters who came out in force for Obama have been cool on Coakley. A large slice of Brown's support has come from independents who voted for Obama in 2008.
Kennedy's passing marked the end of an era, with none of the younger Kennedy generation opting to make a run.
Most of the Democratic primary contenders -- although not Coakley, the winner -- tried to exploit the Kennedy mystique. Kennedy's widow, Vicki, has campaigned for Coakley recently, urging voters to continue her husband's legacy.
But Brown got in the best zinger of the campaign, in a televised debate with Coakley on January 11:
With all due respect, it's not the Kennedys' seat. It's not the Democrats' seat. It's the people's seat.
Voters fed up with political corruption
Coakley has arguably been swept up in backlash against Massachusetts' long history of one-party dominance.
The concentration of power in the hands of the Democratic party has given rise to a series of scandals that have disgusted some normally reliable Democratic voters.
Three consecutive former Massachusetts House speakers have been indicted, and three state senators have resigned in disgrace in the past two years for various infractions.
(Reporting by Ros Krasny; Editing by Mary Milliken and Eric Walsh)