BACKGROUND/OBJECTIVES: Numerous randomised controlled trials (RCTs) published in first tier medical journals have evaluated the health effects of diets high in protein. We conducted a rigorous systematic review of RCTs comparing higher-and lower-protein diets. METHODS: We searched several electronic databases up to July 2011 for studies focusing on patient-important outcomes (for example, cardiovascular disease) and secondary outcomes such as risk factors for chronic disease (for example, adiposity). RESULTS: We identified 111 articles reporting on 74 trials. Pooled effect sizes using standardised mean differences (SMDs) were small to moderate and favoured higher-protein diets for weight loss (SMD - 0.36, 95% confidence interval (CI) - 0.56 to - 0.17), body mass index (- 0.37, CI - 0.56 to 0.19), waist circumference (- 0.43, CI - 0.69 to - 0.16), blood pressure (systolic: - 0.21, CI - 0.32 to - 0.09 and diastolic: - 0.18, CI - 0.29 to - 0.06), high-density lipoproteins (HDL 0.25, CI 0.07 to 0.44), fasting insulin (- 0.20, CI - 0.39 to - 0.01) and triglycerides (- 0.51, CI - 0.78 to - 0.24). Sensitivity analysis of studies with lower risk of bias abolished the effect on HDL and fasting insulin, and reduced the effect on triglycerides. We observed nonsignificant effects on total cholesterol, low-density lipoproteins, C-reactive protein, HbA1c, fasting blood glucose, and surrogates for bone and kidney health. Adverse gastrointestinal events were more common with high-protein diets. Multivariable meta-regression analysis showed no significant dose response with higher protein intake. CONCLUSIONS: Higher-protein diets probably improve adiposity, blood pressure and triglyceride levels, but these effects are small and need to be weighed against the potential for harms.