The incidence of and risk factors for Jarisch-Herxheimer (JH) reaction were investigated prospectively among 240 human immunodeficiency virus (HIV)-infected and 115 HIV-uninfected patients with syphilis who received penicillin treatment. The overall rate of JH reaction was 31.5% (34.6% in HIV-infected patients and 25.2% in HIV-uninfected patients). In multivariate analysis, risk factors for JH reaction included high rapid plasma reagin (RPR) titers (per log(2) RPR increase, risk ratio [RR], 1.19; 95% confidence interval [CI], 1.04-1.37), early syphilis (RR, 8.59; 95% CI, 4.75-15.56), and prior penicillin treatment (RR, 0.39; 95% CI, 0.20-0.78).