The authors conducted a retrospective analysis of a new obesity treatment protocol, metformin and hypocaloric, carbohydrate-modified diet, in high-risk, nondiabetic hyperinsulinemic women with progressive midlife weight gain (refractory to diet and exercise). Thirty consecutive nondiabetic women with glucose-mediated area-under-the-curve (AUC) insulin elevations >>or=100 microU/mL) in two body mass index (BMI) categories (group I: 25 to 32.9 kg/m(2) and group II: 33 to 41.7 kg/m(2)) participated in a 1-year treatment program of metformin (mean daily doses of 1,500 mg/day [group I] and 2,000 mg/day [group II]) and carbohydrate-modified dietary regimens. Follow-up body weight (at 3, 6, and 12 months), percentage of patients meeting goal weight attainment (10% reduction in body weight or BMI normalization), and fasting insulin levels (as available) are reported in 26 women (18/18 in group I and 8/12 in group II) who returned for one or more follow-up visits. Significant weight loss was observed at 3, 6, and 12 months in both group I (3.47 [SE 0.68], 6.41 [0.72], and 8.06 [0.96] kg, P < 0.0001) and group II (4.4 [0.8], 9.7 [2.3], 15.1 [3.3], P = 0.001, 0.004, 0.011). Twenty-five of 26 (96%) patients lost>>or=5% of their body weight at 6 months and 21/26 (81%) patients lost>>or=10% of their body weight at 12 months. Posttreatment fasting insulin decrement (-35.5 [8.2]%) was the most significant predictor of 1-year weight loss (R(2)=0.656, regression coefficient = 0.810, P = 0.005). Following completion of the 1-year intervention study, weight stabilization (within 1 kg) was observed at a 6-month surveillance in 8/9 patients who attained goal weight and continued metformin without additional nutritional counseling, in contrast to weight gain >>or=4 kg or 50% of lost weight) in 5/6 patients who discontinued metformin. The authors concluded that metformin and carbohydrate-modified hypocaloric diet could be an effective novel treatment for long-term weight management in nondiabetic, hyperinsulinemic women.