The development of new pharmaceutical interventions for persons with human immunodeficiency virus (HIV) infection has resulted in extended survival and a need for valid, reliable and responsive instruments to assess health-related QoL (HRQoL). This paper reviews the reliability and validity of an HRQoL instrument, the AIDS Health Assessment Questionnaire (AIDS-HAQ), among persons participating in an observational database of HIV infection. The AIDS-HAQ includes nine subscales: disability, energy, general health, pain, cognitive functioning, mental health, social functioning, health distress and symptoms. Individuals complete the AIDS-HAQ quarterly. Data are reported for 440 individuals entering the study with early HIV infection. Fifty-nine progressed to symptomatic disease and 109 to AIDS after 1 year. The subscales of the instrument resulted in high internal consistency reliability (range = 0.79-0.88). Concurrent validity data reflected the ability to distinguish between patients with increasing disease severity. In all domains, except cognitive functioning, individuals who progressed to AIDS had significant decrements (p < 0.01) in HRQoL compared with symptomatic and asymptomatic patients. Significant decrements (p < 0.01) were observed for disability, general health, energy and symptoms for patients who progressed to symptomatic disease from an asymptomatic status. Individuals who had decreasing CD4+ counts also had significant declines (p < 0.001) in disability, general health, social functioning, pain and symptoms. The AIDS-HAQ is an instrument that can be used when comparing group differences and within group changes in observational databases, naturalistic studies and clinical trials.