Diets with increased protein and reduced carbohydrates (PRO) are effective for weight loss, but the long-term effect on maintenance is unknown. This study compared changes in body weight and composition and blood lipids after short-term weight loss (4 mo) followed by weight maintenance (8 mo) using moderate PRO or conventional high-carbohydrate (CHO) diets. Participants (age = 45.4 +/- 1.2 y; BMI = 32.6 +/- 0.8 kg/m(2); n = 130) were randomized to 2 energy-restricted diets (-500 kcal/d or -2093 kJ/d): PRO with 1.6 g x kg(-1) x d(-1) protein and <170 g/d carbohydrates or CHO with 0.8 g x kg(-1) x d(-1) protein, >220 g/d carbohydrates. At 4 mo, the PRO group had lost 22% more fat mass (FM) (-5.6 +/- 0.4 kg) than the CHO group (-4.6 +/- 0.3 kg) but weight loss did not differ between groups (-8.2 +/- 0.5 kg vs. -7.0 +/- 0.5 kg; P = 0.10). At 12 mo, the PRO group had more participants complete the study (64 vs. 45%, P < 0.05) with greater improvement in body composition; however, weight loss did not differ between groups (-10.4 +/- 1.2 kg vs. -8.4 +/- 0.9 kg; P = 0.18). Using a compliance criterion of participants attaining >10% weight loss, the PRO group had more participants (31 vs. 21%) lose more weight (-16.5 +/- 1.5 vs. -12.3 +/- 0.9 kg; P < 0.01) and FM (-11.7 +/- 1.0 vs. -7.9 +/- 0.7 kg; P < 0.01) than the CHO group. The CHO diet reduced serum cholesterol and LDL cholesterol compared with PRO (P < 0.01) at 4 mo, but the effect did not remain at 12 mo. PRO had sustained favorable effects on serum triacylglycerol (TAG), HDL cholesterol (HDL-C), and TAG:HDL-C compared with CHO at 4 and 12 mo (P < 0.01). The PRO diet was more effective for FM loss and body composition improvement during initial weight loss and long-term maintenance and produced sustained reductions in TAG and increases in HDL-C compared with the CHO diet.