The aim of this study is to assess whether HIV-related illness and World Health Organization (WHO) clinical stage can be used to guide initiation of antiretroviral therapy (ART) in rural Rakai District, Uganda. A retrospective cohort analysis of 910 HIV-seroprevalent individuals randomly sampled from a community cohort was conducted. The associations between HIV-related clinical illness and HIV viral loads >55,000 copies/mL and death were evaluated as a guide for initiation of ART. Reporting one or more HIV-related illnesses was associated with high specificity for identifying HIV viral load >55,000 copies/mL and predicting death within 30 months. There were more deaths in those with one symptom at baseline (16.3%) and two or more symptoms (25.0%) than in those reporting no symptoms (9.6%; P = 0.001).HIV-related illness and WHO stage predicted disease progression. The specificity of clinical illness to predict viral load >55,000 copies/mL was high and could be used to rule in HIV disease requiring ART.