BACKGROUND: For many people, maintenance of weight loss is elusive. Whereas high-protein (HP) diets have been found to be superior to high-carbohydrate (HC) diets for weight loss in the short term, their benefits long term are unclear, particularly for weight maintenance. Furthermore, the literature lacks consensus on the long-term effects of an HP diet on cardiovascular disease risk factors. OBJECTIVE: The objective was to investigate whether macronutrient dietary composition plays a role in weight maintenance and in improvement of cardiovascular disease risk factors. DESIGN: The study comprised 2 phases. Phase 1 featured a very-low-energy diet for 3 mo. In phase 2, the subjects were randomly assigned to an HP or an HC diet for 12 mo. The diets were isocaloric, tightly controlled, and individually prescribed for weight maintenance. The subjects were overweight or obese but otherwise healthy men and women. RESULTS: The subjects lost an average of 16.5 kg during phase 1 and maintained a mean (+/-SEM) weight loss of 14.5 +/- 1.2 kg (P < 0.001) during phase 2; no significant differences between groups were observed. By the end of the study, reductions in systolic blood pressure were 14.3 +/- 2.4 mm Hg for the HP group and 7.7 +/- 2.2 mm Hg for the HC group (P < 0.045). Forty-seven percent of the 180 subjects who began the study completed both phases. CONCLUSIONS: The results indicate that the protein or carbohydrate content of the diet has no effect on successful weight-loss maintenance. A general linear model analysis indicated that dietary treatment (HP or HC) was a significant factor in systolic blood pressure change and in favor of the HP diet. This trial was registered at www.clinicaltrials.gov as NCT 00625236.