In Philadelphia, a large increase in syphilis among minority group heterosexuals began in 1986 and preceded similar increases elsewhere in the United States. To determine reasons for this increase, we conducted a case-control study in the metropolitan sexually transmitted diseases clinic during 1987 and 1988. Cocaine use (odds ratio [OR] 3.1; 95% confidence interval [95% CI] = 1.5, 6.5 among men; OR 5.8; 95% CI = 1.5, 33 among women) and exchange of drugs for sex (OR 3.5; 95% CI = 1.4, 8.7 among men) were risk factors for syphilis. Although cocaine users reported more sexual partners and more frequently reported sex with prostitutes, cocaine use remained a risk factor after adjustment for these behaviors. These data suggest that sexual behavior or another factor, such as availability or utilization of health care, among cocaine users leads to increased risk of syphilis in this population. Increases in cocaine use may be partly responsible for recent increases in syphilis incidence in the United States.