The clash came as about 1,000 demonstrators, mostly farmers and laborers, tried to approach the negotiating venue but were pushed back by police wielding riot shields and firing water cannon.
Some protesters fought with riot-control sticks they had taken from police. In dispersing the crowd, police chased protesters and hit some with riot shields. At least two demonstrators were taken away by ambulance.
The clash follows a smaller one Monday, the first of a scheduled five-day round of talks.
It is the fourth round since June of talks aimed at knocking down tariffs and opening markets between the U.S. -- the world's largest economy -- and South Korea, its 10th-largest.
South Korean rice and beef farmers have especially opposed a deal, saying cheaper U.S. products would jeopardize their livelihoods.
The two sides have said they want to reach a deal by the end of this year, though the chief U.S. negotiator said Monday that the talks may drag into early next year.