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Objective To test the hypothesis that HIV infection impairs the beneficial effects of weight-loss on insulin-sensitivity and adipose-tissue inflammation and endoplasmic reticulum (ER) stress. Methods A prospective clinical trial to evaluate the effects of moderate diet-induced weight-loss on body-composition, metabolic function and adipose-tissue biology in women with obesity who were HIV-seronegative (HIV−) or HIV-positive (HIV+). Body-composition, multi-organ insulin-sensitivity (assessed by using a 2-stage hyperinsulinemic-euglycemic clamp procedure with stable isotopically-labeled tracer infusions), and adipose-tissue expression of markers of inflammation, autophagy and ER stress were evaluated in 8 HIV− and 20 HIV+ women with obesity before and after 6%–8% diet-induced weight-loss. Results Although weight-loss was not different between groups (~7.5%), the decrease in fat-free-mass was greater in HIV+ than HIV− subjects (−4.4±0.7 % vs −1.7±1.0%, P < 0.05). Weight loss improved insulin-sensitivity in adipose-tissue (suppression of palmitate rate of appearance [Ra]), liver (suppression of glucose Ra) and muscle (glucose disposal) similarly in both groups. Weight-loss did not affect adipose-tissue expression of markers of inflammation or ER stress in either group. Conclusions Moderate diet-induced weight-loss improves multi-organ insulin-sensitivity in HIV+ women to the same extent as women who are HIV−. However, weight loss causes a greater decline in FFM in HIV+ than HIV− women.