Assessing health-related quality of life in persons infected with human immunodeficiency virus (HIV) is extremely important, but most available scales are too long, contain items that are not relevant for such persons, or do not assess important signs and symptoms of HIV infection. This study presents a new set of scales for assessing the symptoms and functioning of persons infected with HIV and reports data on their reliability and validity collected in face-to-face interviews with 189 patients receiving primary care. This study also assesses the associations among systems, functional impairment, and global health assessments. The scales are easy to administer, are reliable, and serve as valid measures of quality of life. Fatigue, functional status, and average severity of all symptoms were the best predictors of overall perceived health status. Psychological well-being and perceived health status were the best predictors of overall perceived health status. Psychological well-being and perceived health status were the strongest correlates of life satisfaction. When assessing the health-related quality of life of persons infected with HIV, this study recommends utilizing a comprehensive set of measures that allows one to examine both discrete symptoms and the more diffuse impact of illness on functioning, mental health, and quality of life.