The prevalence of false-positive reactions for syphilis (reactive rapid plasma reagin [RPR] test and nonreactive fluorescent treponemal antibody absorption [FTA-ABS] test) among patients at sexually transmitted disease (STD) clinics was assessed to evaluate the association between false-positive RPR reactions and hepatitis C virus (HCV) infections. Among 2672 patients, 400 (15.0%) had antibodies to HCV (anti-HCV) and 254 (9.5%) had a reactive RPR test. Of the 254 reactive RPR tests, 231 (90.1%) were also positive by FTA-ABS, leaving 23 false-positive RPR reactions. After excluding the 231 patients with positive FTA-ABS tests, false-positive RPR tests were found in 9 (2.7%) of 330 anti-HCV-positive patients compared with 14 (0.6%) of 2154 anti-HCV-negative participants (relative risk, 4.5; 95% confidence interval, 1.9-10.9; P = .0017). These data demonstrate that HCV infection is associated with false-positive RPR test results. However, because of the high prevalence of syphilis among STD patients, the RPR test remains a strong indicator of syphilis in this setting.