The aim of this study was to evaluate the association between acyclovir use and survival in HIV-infected patients. To achieve this, we used survival analysis in an observational cohort of HIV-infected patients enrolled in primary care at an urban HIV clinic. We measured survival in a cohort of HIV-infected patients who had CD4 cell counts < or = 500/mm3 and who enrolled for care at a single urban HIV clinic between December 1988 and April 1995. We compared survival in users of acyclovir alone, zidovudine alone, and acyclovir and zidovudine in combination with the survival of those using neither drug. Factors associated with improved survival were identified using Cox proportional hazards analysis. Among the 1408 patients enrolled, there were no significant differences in overall survival between acyclovir users and non-users. After adjustment for CD4 cell count, the use of other antiretroviral agents, race, transmission risk and a history of herpesvirus infection, acyclovir use alone was independently associated with a relative hazard (RH) of death of 1.008 (P = 0.969); zidovudine use alone with a RH of 0.559 (P < 0.001); and combination use of acyclovir and zidovudine associated with a RH of 1.062 (P = 0.788). Therefore we conclude that the use of acyclovir is not associated with prolonged survival in this cohort of HIV-infected patients.