Primary human immunodeficiency virus type 1 (HIV-1) infection can present clinically as the abrupt onset of a febrile illness resembling acute mononucleosis. The symptoms coincide with high titers of culturable plasma viremia, cell-associated virus, and antigenemia, which rapidly decrease coincident with the emergence of detectable HIV-specific antibody and HIV-specific cytotoxic T lymphocytes. This article reviews the human and animal model data on the virologic and immunologic events that occur during primary HIV-1 and animal retrovirus infections, evaluates the prophylactic treatment experience of retrovirus infections in the animal model, and provides a plausible rationale for treatment intervention of primary HIV-1 infection in humans. Recent work delineating the pathogenesis of primary HIV-1 infection provides insight into the major mechanisms of viral dissemination and host immune response. The results from retrovirus-infected animal models treated with antiviral agents suggests that therapy at the time of viral dissemination may be an effective strategy that may modify disease progression. Clinical trials to evaluate this approach are in progress.