The purpose of this dissertation was to test and develop theoretical models of the relationship between psychological distress and biological markers of HIV-1 pathogenesis in the context of combination antiretroviral therapy (CART). Structural equation modeling (SEM) was used to test plausible pathways through which distress may alter immune regulation and, in turn, account for individual differences in HIV disease severity, defined by HIV-1 viral load and CD4+ helper T-cell count.Two hundred subjects were included in the investigation (mean +/- SD age = 41 +/- 7 yrs; 67% men; 62% Black; mean time since HIV-1 diagnosis = 9 +/- 6 yrs; 31% AIDS based on current CDC Clinical Category C condition). Results revealed a significant association between heightened psychological distress and more severe HIV disease according to standard laboratory biomarkers. This association was largely accounted for by distress-related alterations in immunity. Specifically, higher levels of distress were associated with fewer natural killer cells and elevated systemic inflammation that, together, contributed to increased cytotoxic T-cell activation. Increased cytotoxic T-cell activation, in turn, accounted for substantial variation in disease severity measured at baseline and 9-month follow-up. Observed relationships between distress, immune parameters and disease severity were independent of numerous covariates, including age, sex, race/ethnicity, HIV medication adherence, clinical symptoms of immune deficiency, hepatitis C virus co-infection, and substance use.The present findings suggest a mechanism in which heightened distress may simultaneously tax innate immunity, stimulate inflammation, and activate cytotoxic T-cells, thereby predisposing the HIV+ host to less effective cell mediated immunity, and possibly greater susceptibility to future disease progression. The current data also provide mechanistic evidence to support previous epidemiological research that has identified stress and negative affect as risk factors for accelerated clinical progression of HIV infection. Future studies that longitudinally examine psychosocial risk factors, candidate biological and behavioral mediators, and potential moderators of the psychoimmune effects observed in the present study are necessary to address the methodological shortcomings inherent in this investigation and further extend scientific understanding of biological pathways linking the mind/body in the context of HIV/AIDS.