With about 83% of total ballots accounted for early Monday in Puerto Rico, Romney had garnered more than 98,000 votes -- or 83% of the total -- based on unofficial results obtained from local party and election officials.
The other two candidates, former House Speaker Newt Gingrich and Texas Rep. Ron Paul, were barely registered in the race with 2,431 votes, or 2% of the vote, and 1,452 votes, or 1%, respectively.
Even as the vote was being counted in Puerto Rico, Romney, Santorum and the other candidates were already on the mainland vying for delegates in Illinois and Louisiana.
Illinois holds its primary on Tuesday and Louisiana on Saturday.
CNN's latest delegate estimates show Romney with 518 delegates to Santorum's 239. Gingrich has 139 delegates, and Paul, the libertarian champion, has 69 delegates. To secure the nomination, 1,144 delegates are needed.
Santorum, the former Pennsylvania senator, was in Louisiana late Sunday, where he is expected to win the primary.
Romney was in Illinois where polls indicate he holds a small lead over Santorum, with Gingrich and Paul well behind.
Romney framed his win in Puerto Rico as the territory's desire for a candidate that "most represents their feelings" -- and especially their desire to nominate some who can bring about a stronger economy and a smaller government.
He also said his party can appeal to Latinos, and win the presidency, with a low-tax, pro-business message.
"Those people who don't think that Latinos will vote for a Republican need to take a look in Puerto Rico," said the former Massachusetts governor, noting that the territory's governor and its legislative leaders are conservative.
"Hispanic voters are going to vote for Republicans if we stand for something -- conservative principles that bring growth and good jobs and rising home values. That's how we're going to win, and we're going to get Latino voters to help us out."
Romney had entered the contest in Puerto Rico as the favorite. He was largely backed by the island government's political establishment, including Gov. Luis Fortuno, who campaigned with Romney last week.
Santorum, the former Pennsylvania senator, created a small political firestorm on the island in the days leading up to the primary when he said English should be the principal language in Puerto Rico before it could gain statehood. Puerto Rico will vote on a statehood referendum in November.
After arriving in Puerto Rico on Friday, Romney said he would have "no preconditions" on language for Puerto Rico to gain statehood, though during a CNN debate in January he said English should be the nation's official language.
Santorum immediately hit back, accusing Romney of flip-flopping.
Romney fired back that English has been the official language of the government in Puerto Rico for more than 100 years.
The heated, see-saw allegations between the two candidates have marked much of the race for the GOP nomination, which Sen. John McCain, R-Arizona, called "the nastiest I've ever seen" during an appearance Sunday on NBC's "Meet The Press."