This is a randomized, multicenter, double-blind, placebo-controlled Phase III study to evaluate the effect of valaciclovir in preventing the transmission of herpes simplex virus (HSV) in heterosexual couples discordant for the presence of herpes simplex type 2 virus (HSV-2) antibody. The seropositive source partner will be randomized to receive valaciclovir 500 mg once daily or placebo for 8 months, and the susceptible seronegative partner will be monitored for clinical and subclinical (serological) acquisition of HSV. Couples must be 18 years of age or older, in general good health, and in a monogamous relationship with each other. Source partners must be seropositive for HSV-2, have a history of genital herpes recurrences, and experiencing less than 10 recurrences per year, and be off suppressive therapy upon entry into the study. Susceptible partners must be HSV-2 seronegative. The couple will be stratified based on gender and HSV status of the susceptible partner in a 2:2:1:1 ratio [HSV-1 negative female: HSV-1 positive female: HSV-1 negative male: HSV-1 positive male]. They will then be randomized to either valaciclovir 500 mg once daily or placebo (1:1 randomization) within each stratum. The primary endpoint is the proportion of couples with clinical evidence of a first episode of genital HSV in the susceptible partner with laboratory confirmation. Secondary endpoints will be time to clinical symptoms of genital HSV by the susceptible partner, time to seroconversion in the susceptible partner, and time to first recurrence of HSV in the source partner. A total of 1500 couples will be randomized into the study. Assuming a 3% incidence in the placebo arm and a reduction of 75% in the risk of showing clinical evidence of genital HSV, this study will have at least 80% power for a two-tailed test at the 5% level of significance. The safety and tolerance of valaciclovir will be assessed by laboratory evaluation and by occurrence and nature of adverse events. The study will be conducted at approximately 35 outpatient centers in the United States, Canada and Europe, therefore it is expected that each center will enroll between 40 to 60 couples.