Treatment of recurrent herpes simplex virus (HSV) infection with a vaccine was attempted as early as 1938. The concept of immune therapy is based on the premise that vaccine administration may augment host immunity, resulting in better control of the infection. The guinea pig model is useful in the study of recurrent HSV infection for several reasons. This animal model mimics human infection, with self-limited primary vulvovaginitis developing after inoculation with HSV. Despite a full range of host immune responses, the virus persists in a latent state within sensory ganglia. Periodically, the latent virus reactivates to produce recurrent genital infections. Use of the guinea pig model has made it possible to demonstrate that the administration of HSV glycoprotein vaccines to infected animals results in a significant reduction in the frequency and severity of recurrences. Studies demonstrate that a variety of factors influence the effectiveness of immunotherapy. These factors include not only immunogen and dose but also the route of administration, timing of treatment relative to primary infection, and adjuvant formulation. Investigations of HSV immunotherapy in the guinea pig model provide the first controlled experimental data indicating that vaccine administration to an infected host can favorably alter the natural history of a persistent infection.