Between 1981 and 1989, the incidence of primary and secondary syphilis in the United States increased 34%, from 13.7 to 18.4 cases per 100,000 persons, the highest since 1949. The populations affected most by syphilis also changed substantially. From a peak of 10.0 cases per 100,000 persons in 1982, the incidence among white men had decreased 69% by 1989 (3.2 cases per 100,000 persons). From 1982 to 1985, the incidence also decreased among black men (30%, 101.9 to 71.5 cases per 100,000) and black women (22%, 45.8 to 35.8 cases per 100,000). However, in 1986 this trend reversed, and the incidence among blacks more than doubled from 1985 to 1989 (52.6 to 121.8 cases per 100,000 persons). Racial differences in syphilis incidence increased (black-to-white incidence rate ratio in 1981 was 14.5 and in 1989 was 47.8), as did regional differences. Trends in syphilis incidence indicate changes in sexual behavior that may determine future sexual transmission of human immunodeficiency virus. Targeting resources at populations most affected by this recent epidemic is an urgent public health priority.