The efficacy of anti-herpetic drugs in decreasing HIV disease progression has not been clarified. We studied a cohort of 126 HIV-positive individuals with known date of seroconversion who were HSV-2-seropositive to determine if progression to AIDS was influenced by treatment with acyclovir. In the multivariate analysis, being homosexual and low CD4 count were associated with a faster progression to AIDS, whereas treatment with acyclovir showed a 37.0% protective effect compared to those who did not receive it when antiretroviral treatment was not included in the model. When including antiretroviral therapy, the protective effect of acyclovir decreased to 9.0% and that of antiretroviral therapy was 43.0% for monotherapy and 36.0% for double therapy, suggesting that most of the protective effect of acyclovir in the previous model was due to antiretroviral therapy. In conclusion, treatment with acyclovir does not seem to prolong significantly survival to AIDS among HIV-positive individuals who are HSV-2-infected.