HIV-related fatigue remains the most troubling complaint of seropositive people. Researchers often use tools to measure fatigue that were developed for other patient populations; thus, the measurement of fatigue specific to HIV is needed. This article describes results from the HIV-Related Fatigue Scale (HRFS) including: (a) the variability in intensity and chronicity of HIV-related fatigue, (b) the circumstances surrounding changes in fatigue, (c) the impact of fatigue on activities of daily living (ADLs), and (d) the consequences of HIV-related fatigue. We collected data every 3 months over a 3-year period from 128 people. HIV-related fatigue was chronic and did not appear to remit spontaneously; those who were the most fatigued at the beginning of the study remained the most fatigued over 3 years. Fatigue interfered more with instrumental activities of daily living than basic ADLs; it also interfered with work, family, and social life. Stress and depression increased fatigue.