Our objective was to evaluate valaciclovir for anogenital herpes in HIV-infected individuals using 2 controlled trials conducted before highly active antiretroviral therapy (HAART) was used. In Study 1, 1062 patients (CD4+ > or = 100 cells/mm(3)) received suppressive valaciclovir or aciclovir for one year and were assessed monthly. In Study 2, 467 patients were treated episodically for > or =5 days with valaciclovir or aciclovir and evaluated daily. Valaciclovir was as effective as aciclovir for suppression and episodic treatment of herpes. Hazard ratios [95% confidence interval (CI)] for time to recurrence for valaciclovir 500 mg twice daily and 1000 mg once daily vs aciclovir were 0.73[0.50, 1.06], P=0.10, and 1.31[0.94, 1.82], P=0.11. Valaciclovir 500 mg twice daily was superior to 1000 mg once daily, P=0.001. Valaciclovir 1000 mg twice daily was comparable to aciclovir on herpes episode duration (hazard ratio 0.92[0.75, 1.14]). Adverse events were similar among treatments. In conclusion, valaciclovir is a safe, effective, convenient alternative to aciclovir for HSV infection in HIV-infected individuals.