To determine the efficacy and safety of valacyclovir (500 mg twice daily) for the suppression of recurrent genital herpes simplex virus infections in human immunodeficiency virus (HIV)-infected subjects, a randomized, double-blind, placebo-controlled, multicenter international trial was conducted. A total of 293 HIV-seropositive subjects receiving antiretroviral therapy were enrolled. The proportion of subjects who did not have a recurrence of genital herpes at 6 months was 65% among valacyclovir recipients versus 26% among placebo recipients (relative risk, 2.5; 95% confidence interval, 1.8-3.5). The time to first genital herpes recurrence was significantly shorter in the placebo group (median, 59 days) than in the valacyclovir group (median, >180 days). Valacyclovir was well tolerated; the incidence of adverse events for the 2 treatment groups was similar when the duration of treatment was considered. There were no episodes of thrombotic microangiopathy. Valacyclovir was safe and effective for the suppression of recurrent genital herpes infection in HIV-infected individuals.