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With adherence to combination antiretroviral therapy, HIV infection is now a chronic, but manageable, disease with associated symptoms and complications. However, there is limited evidence on how symptom burden affects perceived overall function among people living with HIV (PLWH). Furthermore, there is no consensus on the factors that affect symptom burden in PLWH. We examined relationships between factors that may influence symptom burden and perceived overall function, and the association between symptom burden and overall function in 179 adult PLWH. This study was a cross-sectional, secondary analysis using the Theory of Unpleasant Symptoms (Lenz, Pugh, Milligan, Gift, & Suppe, 1997). We found strong evidence that symptoms, especially pain, tiredness, and depression, are prevalent in PLWH, and that symptoms were predicted by perceived social support and the number of comorbidities. Increased symptom burden predicts reduced overall function. Interventions are needed to reduce symptoms and strengthen social support in PLWH. Initiating symptom assessment and management strategies early is paramount. [ABSTRACT FROM AUTHOR]