Adipose tissue physiology plays an important role in mediating disease risk. Weight loss in obese individuals improves indicators of adipocyte physiology. However, the minimum degree of weight loss required to elicit improvements remains unknown. The objective of the present study was to determine the minimum weight loss required to improve adipokine profile and decrease fat cell size in severely obese women. Thirteen severely obese women (body mass index, 50 +/- 3 kg/m(2); age, 35 +/- 1 years) consumed a low-calorie diet for 3 weeks with the goal of losing 5% of their initial weight. Subjects were divided into 2 weight loss groups posttreatment: less than 5% weight loss and 5% to 10% weight loss. Body weight was reduced (P < .05) in both groups (-1.4 +/- 1.0 and -6.8 +/- 0.6 kg, respectively). Adiponectin concentrations increased (P < .05) by 20% in the 5% to 10% weight loss group only. Likewise, leptin and resistin decreased (P < .05) by 37% and 27%, respectively, in the group that lost more weight. Visceral and subcutaneous fat cell size was 41% and 37% smaller (P < .01), respectively, in the 5% to 10% weight loss group. Smaller visceral adipocyte size was related to lower insulin (r = 0.82, P = .01) and glucose (r = 0.58, P = .04) concentrations posttreatment. These findings suggest that a minimum weight loss of 5% is required to improve adipokine profile and decrease fat cell size in severely obese women. These changes in adipocyte physiology may be linked to reductions in metabolic disease risk in this population.