ObjectiveTo determine the nature and strength of the relation between lean body mass and measures of health-related quality-of-living (HRQL) including physical functioning in men and women with HIV.DesignCross-sectional analysis using 619 patients with HIV infection from two cities in the northeastern United States.Main Outcome MeasuresLean body mass (LBM) was assessed by bioimpedance analysis (BIA). Physical functioning, general health perceptions, energy/fatigue, and number of days spent in bed in the last month were determined by patient self-report.ResultsData from 450 men and 169 women were analyzed. Mean age was 39 years, 37.6% were nonwhite, and mean CD4 counts were 352 cells/ml. In multivariable models, higher LBM was significantly associated with better physical functioning in men but not in women. In men, a 10-kg increment in LBM was associated with a 3.7 point (95% confidence interval [CI], 0.19–7.2) increment in physical functioning (0–100 scale). In similar analyses, higher LBM was significantly associated with better general health perceptions (10-kg increment in LBM associated with a 4.8 point [95% CI, 1.4–8.1] increment in general health perceptions), and fewer days in bed in the last month (10-kg increment in LBM associated with 0.9 [95% CI, −1.8–0] fewer days in bed). Lean body mass was not independently associated with energy/fatigue.ConclusionsIn this diverse population of persons with HIV, LBM was significantly related to physical functioning and other measures of HQRL in men, but not in women. In men, the relation was linear but relatively weak. These data have potential implications for assessing the clinical impact of interventions aimed at increasing LBM. Even in men, increases in LBM in the ranges that are currently achievable may produce relatively small improvements in physical functioning and other measures of HRQL.