The Washington Post projected Romney the winner, as expected, in the state he governed from 2003 to 2007 and where 38 delegates were up for grabs.
With CNN showing 95 percent of the precincts counted, Romney had 72 percent (246,956 votes) to 12 percent (41,766) for Rick Santorum, 10 percent (32,841) for Ron Paul, 5 percent (15,984) for Newt Gingrich.
Massachusetts' delegates will be awarded proportionately.
Speaking to supporters in Boston Tuesday night, Romney said his campaign is headed for victory in the GOP nomination battle.
"Your support means everything to me and I'm not going to let you down," he said. "I'm going to get this nomination."
Romney also was the projected winner in Virginia and Vermont, the Post said.
"Tonight we've taken one more step toward restoring the promise of America. Tomorrow we wake up and we start again," the Boston Herald quoted Romney as saying. "And the next day we do the same. And so it will go, day by day, step by step, door to door, heart to heart.
"There will be good days and bad days, always long hours and never enough time. But, on November 6, we will stand united, not only having won an election but having saved a future," he said.