As polls closed across the state, exit polling showed Gingrich ahead of the former Massachusetts governor overall, and leading by a wide margin among the state's conservatives, tea party supporters and born-again Christians.
Former Pennsylvania Sen. Rick Santorum garnered 17 percent of voters and Texas Rep. Ron Paul got 13 percent to round out the field in a campaign defined by its unpredictability.
For their parts, the Republican candidates hit the ground running in a last-minute scramble for votes in the morning. Romney met with supporters at Tommy's Country Ham House in Greenville. Gingrich made an appearance at the same restaurant a short time later.
"I am the only conservative who has an opportunity to stop a Massachusetts moderate," said Gingrich at The Grapevine restaurant in Boiling Springs. "And I need the vote of every conservative in South Carolina today."
"Speaker Gingrich worked for Fannie Mae and Freddie Mac. Didn't he say he was going to release information about his relationship there?" said Romney. "Let's see what report he wrote for Fannie Mae and Freddie Mac. What his conclusions were and what the contract looked like. I thought he said he was going to do that."
The Florida primary is in nine days. The next debate is Monday night in Tampa.
Meanwhile, Santorum braced for a setback after getting the most votes in Iowa and besting Gingrich in New Hampshire.
Paul made plans to focus on states where his libertarian, Internet-driven message might find more of a reception with voters; his campaign said it had purchased a substantial ad buy in Nevada and Minnesota, which hold caucuses next month.
Since 1980, every candidate who has won South Carolina's Republican primary has gone on to capture the GOP presidential nomination.
Meantime, a South Carolina prosecutor says officials will launch an investigation into fake emails, claiming to be from Gingrich's campaign.
One of the bogus emails claims that Gingrich had forced his ex-wife Marianne to terminate a pregnancy. At a campaign stop Friday night, Gingrich called the fake emails "disgusting" and said the offenders should be prosecuted.
After the investigation is completed, the information will be turned over to the South Carolina Attorney General, who will decide if any laws were violated.
Marianne burst into the campaign this week when she alleged in an ABC News interview that her former husband had asked her for an "open marriage," a potentially damaging claim in a state where the Republican primary electorate includes a potent segment of Christian conservatives. The thrice-married Gingrich, who has admitted to marital infidelities, angrily denied her accusation.
The Associated Press contributed to this story.