Studies of HIV-related symptom and treatment side effect prevalence often fail to distinguish individual causal attributions between the two types of problems. However, an understanding of causal appraisals is critical to clarifying and intervening on coping in the context of HIV symptoms and treatment side effects. The objectives of this study are (1) to present causal attributions of symptoms reported by HIV+ adults taking combination therapy and (2) to describe the differential impact on health-related quality of life. In a cross-sectional interview study, a convenience sample of 109 HIV-positive adults taking highly active antiretroviral therapy (HAART) were interviewed using a combination of self- and interviewer-administered measures of quality of life, physical problem checklists, and side effect and HIV-related symptom attribution assessments. The most prevalent physical problems were fatigue, stiff/painful joints, aching muscles, diarrhea, feelings of depression, and neuropathy. Those most commonly labeled as side effects of HAART included upset stomach, nausea/vomiting, constipation, and changes in taste. Most commonly cited as symptoms related to HIV disease were tender lymph nodes, night sweats, weight loss, fever, and loss of strength. Impact of side effects, symptoms, and both were associated with impaired physical and social functioning. Disease-related symptoms, but not side effects, were related to perceptions of general health. Results suggest that HIV-positive persons taking HAART make distinctions between symptoms of disease and side effects of treatment. Perceived disease-related symptoms and side effects have significant and unique associations with quality of life. Findings have implications for symptom and side effects management, provider relations, and future research.