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Long-term weight reduction remains the ultimate objective and challenge of obesity management. Few long-term dietary or pharmacointervention studies have been conducted and there is a critical need for long-range treatment strategies that are effective, safe, and acceptable. The authors conducted a retrospective cohort analysis of 21 euglycemic, hyperinsulinemic women with progressive, refractory, midlife weight gain (Syndrome W) who had previously lost weight (≥10% reduction from baseline) with a comprehensive 1-year treatment program that included metformin and a hypocaloric, carbohydrate-modified (low-glycemic index) diet, as well as, other lifestyle modifications. The goal of the analysis was to determine long-term efficacy of the composite intervention using NHLBI criteria for weight stabilization, weight regain ≤3 kg (6.6 lb) in 2 years. Of a total of 26 consecutive women with Syndrome W who achieved goal weight during a 3-year period (1998–2001), 21 women (mean [standard error] age, 55.2 [2.4] years; mean body mass index, 34.2 [1.3] kg/m2) continued metformin and returned for annual follow-up visits. Weight maintenance was observed at the final (2–4 year) follow-up visit in 19/21 (90.5%) of women. Mean final follow-up weight (77.5 [2.8] kg) correlated highly with mean weight at 1-year protocol completion (77.2 [2.7] kg), (correlation coefficients rxy and σxy = 0.96, P = 0.000), demonstrating long-term weight reduction in the surveillance phase. Significant and robust decrements in fasting insulin (-28.4% [8.1%] to −43.4% [3.7%]) were observed at all follow-up visits (P ≤ 0.002). This preliminary case series suggests that metformin may be an effective long-term adjunct to dietary and other interventions in the treatment of obesity in hyperinsulinemic patients. A randomized clinical trial of the dual regimen should be considered in nondiabetic women with midlife weight gain and hyperinsulinemia (Syndrome W) and, quite possibly, in additional euglycemic overweight and obese subjects with documented hyperinsulinemia and other portentous features of the Metabolic Syndrome.