To determine the efficacy of a herpes simplex virus type 2 (HSV-2) glycoprotein subunit vaccine, vaccine (50 micrograms) or placebo was administered intramuscularly at weeks 0, 4, and 22 to 161 persons who lacked HSV-2 antibodies and were sex partners of persons with recurrent genital herpes. The annual rate of acquisition of HSV infection was similar among vaccine and placebo recipients (10.7% and 8%, respectively) but was higher in initially seronegative subjects (15.5%) than in those with HSV-1 at entry (5.9%). Eleven (79%) of the 14 HSV infections acquired during follow-up were symptomatic. Vaccination elicited ELISA antibody titers to glycoproteins gD2 and gB2 that were only 10% and 5%, respectively, of titers found in persons with recurrent genital HSV-2 infection. This vaccine failed to provide protection from acquisition of genital HSV infection. The lack of efficacy appears to be related, in part, to the poor immunogenicity of the vaccine.