Changes in quality-of-life perceptions and their relations to clinical status for 41 adult outpatients living with HIV/AIDS were assessed over a 4-year period. Clinical variables and quality-of-life (Medical Outcomes Study Short-Form-36) ratings were measured in three waves (T1, 1997; T2, 1999; T3, 2001). Mean T1-T3 CD4 increase was 196 cells/microL (p < .0001), corresponding to a mean viral load reduction of 1.4 log10 copies/mL (p < .0001) and an increase in proportions with "undetectable" viral load status from 32% to 61% (p < .01). The T1-T2 increase in overall mean number of symptoms (including both disease-related symptom complex and treatment side effects) was mitigated by T2-T3 symptom reduction. Quality-of-life dimensions were generally stable or slightly improved over time for the overall sample, a finding that contrasts with pre-highly active antiretroviral therapy longitudinal research. Mental aspects of quality of life remained consistently lower than reference norms. Results of multiple regression suggested that quality of life was less sensitive to immunologic/virologic changes compared to responsiveness to symptom changes, consistent with cross-sectional inverse relations between symptom burden and quality of life. CD4 repletion offset negative effects of symptoms for some aspects of quality of life. The long-term course of quality of life was somewhat predicted by viral load suppression due to the conjoint influence of symptoms and CD4 count.