Pioglitazone, a thiazolidinedione (TZD) commonly used to treat type 2 diabetes, is associated with weight gain. Our study was designed to examine the effectiveness of three lifestyle-treatment programs of varying intensity on prevention of pioglitazone-induced weight gain and to measure the composition of the change in body weight. Thirty-nine adult overweight and obese subjects with type 2 diabetes mellitus were all treated with pioglitazone and prospectively randomized to one of three lifestyle-treatment programs with increasing level of intensity for 24 weeks. Body composition was measured by dual-energy X-ray absorptiometry (DXA), computed tomography, and multifrequency bioimpedance analysis both before and after therapy. Subjects demonstrated a "dose-response" effectiveness to three levels of lifestyle intervention to mitigate pioglitazone-induced weight gain. Mean (s.d.) weight change (kg) for the usual, standard, and intensive lifestyle groups were 4.9 +/- 4.9 (P = 0.005), 1.8 +/- 3.4 (P = 0.02), and -0.2 +/- 4.4 (NS) respectively. Total body fat increased 2.6 +/- 3.4 kg (P = 0.04) for the usual group and decreased for the intensive group -0.4 +/- 3.5 (NS). Change in abdominal subcutaneous and visceral adipose tissue (VAT) did not differ between groups, although ratio of visceral/subcutaneous fat decreased for the standard and intensive groups (NS). Both usual (P < 0.05) and standard care (NS) groups gained total body water. This is the first prospective, randomized study that demonstrates the beneficial effect of participation in a comprehensive lifestyle-weight-management program on lessening of weight gain associated with pioglitazone.