The authors suggest a theoretical model of pathways of HIV progression, with a focus on the contributions of depression--as well as secondary, behavioral and emotional variables. Literature was reviewed regarding (a) comorbid depression and the direct physiological effects on HIV progression and (b) intermediary factors between HIV and disease progression. Intermediary factors included (a) substance use, (b) social support, (c) hopelessness, (d) medication nonadherence, and (e) risky sexual behavior and the contraction of secondary infections. The authors suggest direct physiological pathways from depression to HIV progression and indirect pathways (e.g., behavioral, social, and psychological). In addition to depression, substance use, poor social support, hopelessness, medication nonadherence, and risky sexual behavior seem to be integral in HIV progression. Based on the individual relationships of these variables to depression and HIV progression, a comprehensive multipath model, incorporating all factors, serves to explain how severe emotional distress may lead to accelerated progression to AIDS. (Contains 1 figure.)