BACKGROUND It is currently unclear whether altering the carbohydrate-to-protein ratio of low-fat, energy-restricted diets augments weight loss and cardiometabolic risk markers. OBJECTIVE The objective was to conduct a systematic review and meta-analysis of studies that compared energy-restricted, isocaloric, high-protein, low-fat (HP) diets with standard-protein, low-fat (SP) diets on weight loss, body composition, resting energy expenditure (REE), satiety and appetite, and cardiometabolic risk factors. METHODS Systematic searches were conducted by using MEDLINE, EMBASE, PubMed, and the Cochrane Central Register of Controlled Trials to identify weight-loss trials that compared isocalorically prescribed diets matched for fat intake but that differed in protein and carbohydrate intakes in participants aged ≥18 y. Twenty-four trials that included 1063 individuals satisfied the inclusion criteria. RESULTS Mean (±SD) diet duration was 12.1 ± 9.3 wk. Compared with an SP diet, an HP diet produced more favorable changes in weighted mean differences for reductions in body weight (-0.79 kg; 95% CI: -1.50, -0.08 kg), fat mass (FM; -0.87 kg; 95% CI: -1.26, -0.48 kg), and triglycerides (-0.23 mmol/L; 95% CI: -0.33, -0.12 mmol/L) and mitigation of reductions in fat-free mass (FFM; 0.43 kg; 95% CI: 0.09, 0.78 kg) and REE (595.5 kJ/d; 95% CI: 67.0, 1124.1 kJ/d). Changes in fasting plasma glucose, fasting insulin, blood pressure, and total, LDL, and HDL cholesterol were similar across dietary treatments (P ≥ 0.20). Greater satiety with HP was reported in 3 of 5 studies. CONCLUSIONS Compared with an energy-restricted SP diet, an isocalorically prescribed HP diet provides modest benefits for reductions in body weight, FM, and triglycerides and for mitigating reductions in FFM and REE.