Findings of a randomized phase III clinical trial demonstrate that a vaginally-applied topical gel containing the antimicrobicide tenofovir can prevent the transmission of herpes simplex virus type 2 (HSV-2), when used pericoitally. HSV-2 transmission was reduced from 21.0 to 10.2 cases per 100 person-years in women using this gel during unprotected sexual intercourse, significantly reducing the risk of genital ulcer disease in these women.