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. Design: 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, 20.12 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. Conclusion: 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.