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HIV-related fatigue is a debilitating and disabling symptom that persists for months and years. In 743 HIV/AIDS patients from Southern Africa, the authors found ratings of HIV-related fatigue to be highly prevalent. The authors conducted a secondary data analysis within the theoretical context of the University of California, San Francisco Symptom Management Model. The analysis focused on 538 patients who reported fatigue to investigate correlates and predictors of fatigue severity in relationship to demographic and HIV/AIDS illness indicators, as well as HIV-specific physical and psychological symptoms. A hierarchical regression model explored the contributions of those five blocks on fatigue severity. Of the 47% of the total variance in fatigue severity, a combination of variables within the health and illness block (6%), the physical symptoms block (7%) and the psychological symptom block (2%) contributed significantly to the increase in fatigue severity scores. Fatigue severity in Southern Africa was moderate, and the factors contributing to the perceived fatigue were most likely related to symptoms of acute HIV disease (such as fever and gastrointestinal problems). In conclusion, fatigue severity is less impacted by demographic or environmental variables but much more by co-occurring symptoms and HIV disease severity. The results of this study imply the need for more research to understand if improvements in water quality and access to food would prevent infection and diarrhea and whether sufficient access to antiretroviral treatments to manage the HIV infection would improve fatigue and co-occurring symptom profiles.