The only US licensed vaccine with established efficacy against smallpox, Dryvax, is contraindicated for HIV patients. Detectable smallpox-neutralizing antibodies are still present among US adults. This study compared vaccinia-neutralizing antibody titers between 20 HIV-infected and 20 uninfected veterans matched for age and military entry. Vaccinia-neutralizing antibodies were detected in 95% HIV-infected and 100% uninfected veterans; 40% HIV-infected and 70% uninfected adults had protective titers. Therefore, after robust vaccination, neutralizing antibodies are maintained for prolonged times despite CD4 cell depletion.