BACKGROUND: Health-related quality of life refers to how well people are able to perform daily activities (functioning) and how they feel about their lives (well-being). The relationship between symptoms and health-related quality of life has not been fully explored. OBJECTIVE: To estimate the association of HIV symptoms with health-related quality of life and with disability days. DESIGN: Prospective cohort study. SETTING: HIV providers in 28 urban and 24 rural randomly selected sites throughout the United States. PATIENTS: Nationally representative sample of 2267 adults with known HIV infection who were interviewed in 1996 and again between 1997 and 1998. MEASUREMENTS: Symptoms, two single-item global measures of health-related quality of life (perceived health and perceived quality of life), and disability days. RESULTS: White patches in the mouth; nausea or loss of appetite; persistent cough, difficulty breathing, or difficulty catching one's breath; and weight loss were associated with more disability days and worse scores on both health-related quality-of-life measures. Headache; pain in the mouth, lips, or gums; dry mouth; and sinus infection, pain, or discharge were associated with worse perceived health. Pain in the mouth, lips, or gums; trouble with eyes; pain, numbness, or tingling of hands or feet; and diarrhea or loose or watery stools were associated with worse perceived quality of life. Headache and fever, sweats, or chills were associated with more disability days. CONCLUSIONS: Several symptoms are associated with worse health-related quality of life and more disability days in persons with HIV infection. In such patients, targeting specific symptoms may improve health-related quality of life and reduce disability.