Weight regain often occurs after weight loss in overweight individuals. We aimed to compare the effectiveness of 2 support programs and 2 diets of different macronutrient compositions intended to facilitate long-term weight maintenance. Using a 2 x 2 factorial design, we randomly assigned 200 women who had lost 5% or more of their initial body weight to an intensive support program (implemented by nutrition and activity specialists) or to an inexpensive nurse-led program (involving "weigh-ins" and encouragement) that included advice about high-carbohydrate diets or relatively high-monounsaturated-fat diets. In total, 174 (87%) participants were followed-up for 2 years. The average weight loss (about 2 kg) did not differ between those in the support programs (0.1 kg, 95% confidence interval [CI] -1.8 to 1.9, p = 0.95) or diets (0.7 kg, 95% CI -1.1 to 2.4, p = 0.46). Total and low-density lipoprotein (LDL) cholesterol levels were significantly higher among those on the high-monounsaturated-fat diet (total cholesterol: 0.17 mmol/L, 95% CI 0.01 to 0.33; p = 0.040; LDL cholesterol: 0.16 mmol/L, 95% CI 0.01 to 0.31; p = 0.039) than among those on the high-carbohydrate diet. Those on the high-monounsaturated-fat diet also had significantly higher intakes of total fat (5% total energy, 95% CI 3% to 6%, p < 0.001) and saturated fat (2% total energy, 95% CI 1% to 2%, p < 0.001). All of the other clinical and laboratory measures were similar among those in the support programs and diets. A relatively inexpensive program involving nurse support is as effective as a more resource-intensive program for weight maintenance over a 2-year period. Diets of different macronutrient composition produced comparable beneficial effects in terms of weight loss maintenance.