Fatigue is one of the most common and debilitating symptoms experienced by HIV-infected people. We report the results of our longitudinal analysis of physiological and psychosocial factors that were thought to predict changes in HIV-related fatigue in 128 participants over a 1-year period, in an effort to sort out the complex interplay among a comprehensive set of physiological and psychosocial variables. Physiological measures included hepatic function (aspartate aminotransferase, alanine aminotransferase, gamma glutamyl transpeptidase, alkaline phosphatase, total bilirubin, hepatitis C status), thyroid function (thyroid stimulating hormone, thyroxine), HIV viral load, immunologic function (CD4, CD8, CD4/CD8 ratio, CD16, CD8CD38), gonadal function (testosterone, dehydroepiandrosterone), hematologic function (hemoglobin, hematocrit, serum erythropoietin), and cellular injury (lactic acid). Psychosocial measures included childhood and adult trauma, anxiety, depression, social support, stressful life events, and post-traumatic stress disorder (PTSD). Unemployment, not being on antiretroviral therapy, having fewer years since HIV diagnosis, more childhood trauma, more stressful life events, less social support, and more psychological distress (e.g., PTSD, anxiety and depression) put HIV-infected persons at risk for greater fatigue intensity and fatigue-related impairment in functioning during 1-year follow-up. Physiological variables did not predict greater fatigue. Stressful life events had both direct and indirect effects on fatigue.