Obese subjects with non-insulin-dependent diabetes mellitus (NIDDM) lose weight soon after diagnosis and tend to gain weight during hypoglycemic therapy. One explanation for these weight shifts is the change in caloric loss from glycosuria. We compared 24 obese Pima Indians with NIDDM to 24 Pima Indians with normal glucose tolerance to determine whether resting metabolic rate changes may be an additional factor influencing the weight shifts. The diabetic and nondiabetic subjects were equally obese, body fat 38 ± 1% versus 37 ± 1% (mean ± SEM), respectively, as determined by densitometry. In the morning after an overnight fast, resting metabolic rate (RMR) was measured by indirect calorimetry. The mean RMR of the diabetic subjects, 32.9 ± 0.5 kcal/day · kg fat-free mass (FFM), was 5% higher than that of the nondiabetic subjects, 31.4 ± 0.5 kcal/day kg FFM (P < 0.05). In nine of the diabetic subjects, 6 wk of tolazamide therapy was associated with reductions in mean FPG, 253 ± 16 to 144 ± 14 mg/dl (P < 0.01), mean daily urine glucose loss, 128 ± 26 to 11 ± 4 g (P < 0.01), and mean RMR, 31.9 ± 0.8 to 30.2 ± 0.6 kcal/day kg FFM (P < 0.04). Weight of the subjects was maintained constant from beginning to end of therapy (106.5 ± 9.6 versus 108.1 ± 9.9 kg) by decreasing daily calorie intake from 3070 ± 103 to 2784 ± 163 kcal (P < 0.01). We conclude that RMRs of obese, NIDDM subjects are increased compared with the RMRs of equally obese, nondiabetic subjects and that tolazamide therapy that decreases FPG reduces RMR in obese subjects with NIDDM.