The use of antiviral medications has increased with the recognition and treatment of HIV infections, and these drugs are the main focus of this chapter. HIV has become a chronic disease, and many men with HIV desire children. The disease itself has profound negative effects on semen quality, as does infection with hepatitis C virus (HCV), so treatment with antivirals generally improves semen quality in men with longer duration of infection and/or greater symptoms. Several changes in medical practice have allowed studies of pharmacopathology of antiviral medications and brought focus on medication effects in asymptomatic men: (1) the successful practice of specialized sperm washing of asymptomatic men with HIV infection for insemination of their HIV-negative partner; (2) the recommendation that men begin anti-retroviral treatment before HIV symptoms appear; and (3) the recommendation that men without HIV infection who have HIV-seropositive partners take HIV prophylaxis. Early cases of HIV infection were generally treated by monotherapy with the nucleoside analog reverse transcriptase inhibitor (NRTI) zidovudine (AZT). Currently, men with HIV infections take combination anti-retroviral therapy (cART), involving three or more medications, making it difficult to assess the toxicity of individual medications. In general, zidovudine alone or cART have minimal negative effects on semen quality; the most common being decreased rapid swimming of motile sperm. We review studies with other outcomes and animal studies in this chapter. Peginterferon-α, which is utilized together with ribavirin to treat HCV, does appear to decrease testosterone levels and semen quality although studies showing these effects have been small. Antiviral medications used to treat viral infections other than HIV and HCV have received little experimental attention for male reproductive effects, even in experimental species.