Several thousand workers, farmers and students carried banners and chanted slogans against the proposed agreement, which the two governments say will boost economic growth and trade, but opponents say will harm the livelihoods of farmers and workers.
"Stop the South Korea-U.S. FTA," the crowd, estimated by police at about 3,000 people, shouted in the middle of a busy thoroughfare in the capital, snarling traffic.
Police, who have deemed anti-free trade protests illegal and vowed to arrest violators, issued a warning for the crowd to disperse. The protesters began to break up but planned to gather at other locations.
Security around Seoul was heavy.
A National Police Agency official, who spoke on condition of anonymity citing protocol, said 18,000 riot police were being mobilized across the city to prevent protests. He said 12,000 were to be positioned around the hilltop hotel where negotiators were meeting.
The two sides are hoping to conclude an agreement to slash tariffs and other trade barriers by the end of this month. If they succeed, it would be the biggest such deal for Washington since the North American Free Trade Agreement in 1993.
Seoul and Washington say an agreement will boost economic growth and trade between two countries that already do $72 billion in trade a year. South Korea is the United States' seventh-largest trading partner.
Any agreement needs to be approved by South Korea's National Assembly and the U.S. Congress to take effect.
Negotiators were meeting for a third day Saturday. The current round of talks, the eighth since negotiations began last June, is to run through Monday and is the last formal round, the chief U.S. negotiator said Thursday.
Yoo Mi-jung, a senior at Seoul's Sungkyunkwan University who joined Saturday's rally, said she was concerned that an agreement would hurt South Korean workers.
"I think the FTA is going to have a great effect on our life in a bad way," she said.
Associated Press writer Jae-Soon Chang contributed to this report.