Background: The aim of this study was to measure changes in body cell mass (BCM) and quality of life in HIV-infected individuals undergoing oxandrolone therapy. Previous studies on oxandrolone have neither quantified changes in BCM using criterion methods nor quality of life using an HIV-specific instrument. Methods: Twenty-five HIV-infected patients (15 with an AIDS diagnosis) on standard antiretroviral and nutrition management were studied before and an average of 18.6 weeks after the initiation of oxandrolone therapy, as prescribed by their primary care physician for the treatment of weight loss. BCM was estimated from intracellular water measured by multiple dilution. Lean soft-tissue mass (LTM) was measured by dual-energy X-ray absorptiometry. Quality of life was evaluated by the Functional Assessment of HIV Infection (FAHI) questionnaire. Results: Significant gains in body weight (2.6 ± 3.0 kg; p <.0001), BCM (3.6 ± 3.0 kg; p <.0001), and LTM (3.0 ± 2.9 kg; p <.0001) occurred over an average course of 18.6 weeks of treatment. Overall quality of life improved (p =.056) and appetite improved (p =.032), both of which were positively associated with weight gain (p =.040 and p =.022, respectively). Conclusions: This is the first study involving oxandrolone therapy in HIV infection to document changes in quality of life and BCM, the metabolically active component of lean body mass that reflects nutritional status better than other more global body composition parameters. Nutritional status and quality of life can improve in HIV-infected individuals receiving a combined therapeutic approach that includes oxandrolone.