The prevalence of biologic false-positive (BFP) reactions for syphilis (reactive rapid plasma reagin [RPR] test, nonreactive fluorescent treponemal antibody absorption [FTA-ABS] test) among patients attending two sexually transmitted disease (STD) clinics was evaluated to assess relationships between BFP reactions and human immunodeficiency virus (HIV) infection. Among 4863 patients, 357 (7.3%) had serologic evidence of syphilis and 4.9% had HIV infection. Only 40 patients (0.8% of total patients, 11% of those with reactive RPR tests) had BFP serologic tests for syphilis. There were no demographic differences between true syphilis and BFP patients as to sex, age, or intravenous drug use. BFP patients tended to have lower RPR titers (≤1:4) than did true syphilis patients. After excluding 317 patients with reactive FTA-ABS tests, BFP RPR tests were seen in 6 (4%) of 159 HIV-seropositive patients and 34 (0.8%) of 4387 HIV-seronegative patients (odds ratio, 5.0; 95% confidence interval, 1.9-12.7). Although more common among HIV-infected than HIV-uninfected patients, BFP reactions are relatively rare among STD clinic patients, and 89% of patients with reactive RPR or VDRL serologic tests for syphilis had current or prior syphilis infection. The RPR test remains useful for guiding decisions regarding therapy for syphilis. © 1992 The University of Chicago.