OBJECTIVE: The variability of the decline in immune function among those infected by HIV raises the possibility that psychological factors might help to explain the differences. Since studies of other populations have shown natural killer (NK) cells to be affected by psychiatric conditions, the authors examined this relationship in the context of HIV infection, expecting to find fewer NK cells to be associated with greater psychological distress. METHOD: Forty-six HIV- negative and 74 HIV-positive gay men who were participating in a longitudinal study had NK cells enumerations performed (by staining for CD56) 36 months after entry into the study. Comparisons were made between HIV-negative, HIV-positive asymptomatic, and HIV-positive symptomatic men by using a variety of clinician-rated and self-report measures of psychological function and absolute NK cell number. RESULTS: HIV-negative men had more NK cells than the groups of HIV- positive men. The groups' measures of psychological distress did not differ in any clinically meaningful ways. In general, the presence of DSM-III-R diagnoses and the measures of distress did not relate to NK cell number. CONCLUSIONS: NK cell number is not related to measures of psychological distress in these gay men with and without HIV infection.