The seat became vacant when U.S. Sen. Jim DeMint resigned from his Senate seat late last year. Governor Nikki Haley then appointed the sitting congressman, Tim Scott, to fill DeMint's seat.
Colbert Busch had said after she voted in Mount Pleasant, across the Cooper River from Charleston, that she felt positive and encouraged. But in the end, despite Sanford's past being an issue for some voters, she was defeated.
Gabriel Guillard, 49, a massage therapist and teacher, said she liked Colbert Busch but would have voted for anyone but Sanford.
"I would do anything to make sure Mark Sanford doesn't get back in because of his past behavior," she said. "And I am so tired of South Carolina being a laughingstock. I'm so sick of it."
Others didn't let the past dictate. Marion Doar, 79 and retired from careers in the military and business, said he voted for Sanford.
"Sanford was a fine fellow," he said. "He still is a fine fellow. Following his heart as he did was foolish but it happens."
Sanford already has survived a 16-way GOP primary with several sitting state lawmakers and Teddy Turner, the son of media magnate Ted Turner. He also won the primary runoff. Colbert Busch defeated perennial candidate Ben Frasier with 96 percent of the vote in the Democratic primary.
Colbert Busch, 58, picked up the endorsement of The Post and Courier over the weekend. The Charleston newspaper called her "a welcome tonic" for those who suffer from "Sanford Fatigue — a malady caused by overexposure to all of the cringe-worthy details of his 2009 disgrace as governor, his ongoing efforts for redemption via the political process, his resurgent personal problems, etc."
Sanford, despite losing national GOP support, picked up the endorsement of Kentucky Sen. Rand Paul, a tea party favorite who is well-known in the district.