Despite the use of laboratory markers in estimating HIV prognosis, significant variation in the natural history of HIV-1 infection remains unexplained. Recent studies suggest psychosocial risk factors have important prognostic significance in HIV disease. The objective of the present study was to examine the prognostic influence of age, general intellectual functioning, and emotional distress across the spectrum of HIV disease progression. The study sample was drawn from the Multicenter AIDS Cohort Study (MACS), a 13-year, prospective study of HIV-seropositive men recruited from four study centers across the country. The participants were 1,231 HIV-seropositive MACS participants, followed from baseline (median 8/15/87) to the end of the observation period (12/15/98). HIV disease progression was evaluated with respect to three outcome measures: (1) number of years from baseline testing to the first AIDS defining illness (progression to AIDS), (2) years from baseline to HIV-dementia (progression to dementia), and (3) years from baseline to death (survival). The influence of psychosocial risk factors on outcome measures was evaluated using survival analyses. General intellectual functioning, age, and somatic symptoms of depression, were found to be significant predictors of HIV disease progression and survival. Older age at baseline was associated with a more rapid progression to dementia and death. Lower Shipley IQ estimates were associated with a more rapid disease progression (AIDS and dementia) and shortened survival. Somatic symptoms of depression were associated with shortened survival. In addition, age, IQ, and somatic symptoms of depression, had an additive effect with an increase in the number of risk factors associated with accelerated disease progression and shortened time to death. These findings remained consistent, despite controlling for baseline CD4 and HIV medication use. Psychosocial cofactors are important in understanding HIV disease progression. Methods for estimating HIV prognosis may become more reliable if psychosocial factors are considered. Future research will clarify if psychosocial risk factors reflect central nervous system integrity, brain reserve capacity or mediate morbidity and mortality through social economic status, access to health care and other social correlates.