Neutrophil (PMNL) superoxide (O2-) production was evaluated in 71 patients with human immunodeficiency virus (HIV) infection at different stages of disease. In vitro O2- production was significantly depressed for PMNL isolated from HIV-positive patients compared with control PMNL at rest and after stimulation. The degree of impairment of O2- production was more pronounced for patients with lower absolute CD4+ lymphocyte counts. Antiretroviral therapy with zidovudine was also associated with impaired O2- production, but this may reflect a longer duration of disease for treated patients. Zidovudine had no direct inhibitory effect on O2- production by control PMNL in vitro, and serial measurements of O2- production by PMNL from patients before and after initiation of zidovudine did not demonstrate an in vivo inhibitory effect. Impaired PMNL oxidative metabolism in HIV infection may contribute to the increased risk of serious bacterial infections, certain opportunistic infections, and perhaps the pathogenesis of HIV infection itself.