Immunocellular mechanisms that account for the association between psychosocial risk factors and increased susceptibility to faster progression of HIV/AIDS are largely unknown. This study used structural equation modeling to test the hypothesis that enumerative and functional alterations in killer lymphocytes mediate the relationship between higher levels of psychological distress (defined by perceived stress, anxiety and depressive symptoms) and greater HIV disease severity (defined by HIV-1 viral load and T-helper (CD4(+)) cell count), independent of standard demographic and various HIV-related covariates. Participants were 200 HIV-1 seropositive adults on combination antiretroviral therapy (ages 20-55 years; 67% men; 62% black; 84% AIDS). The data fit a psychoimmune model in which the significant relationship between higher distress levels and greater disease severity was mediated by diminished natural killer (NK) cell count and cytotoxic function, as well as increased cytotoxic (CD8(+)) T-cell activation. Overall the findings indicated that the psychoimmune model accounted for 67% of the variation in HIV disease severity. In contrast, the data did not support a reverse directionality mediation model, where greater HIV disease severity predicted greater distress as a function of killer lymphocyte status. In sum, the psychoimmune associations of the final model are physiologically consistent and suggest that distress-related alterations in killer lymphocyte immunity may play a role in the biobehavioral mechanisms linked with HIV-1 pathogenesis.