Background: Meta-analyses of short-term studies indicate favorable effects of higher protein vs. lower protein diets on health outcomes like adiposity or cardiovascular risk factors, but their long-term effects are unknown. Methods: Electronic databases (MEDLINE, EMBASE, Cochrane Trial Register) were searched up to August 2012 with no restriction to language or calendar date. A random effect meta-analysis was performed using the Software package by the Cochrane Collaboration Review Manager 5.1. Sensitivity analysis was performed for RCTs with a Jadad Score ≥3, and excluding type 2 diabetic subjects (T2D). Results: 15 RCTs met all objectives and were included in the present meta-analysis. No significant differences were observed for weight, waist circumference, fat mass, blood lipids (i.e. total cholesterol, LDL-cholesterol, HDL-cholesterol, triacylglycerols), C-reactive protein, diastolic and systolic blood pressure, fasting glucose and glycosylated hemoglobin. In contrast, improvements of fasting insulin was significantly more pronounced following high protein diets as compared to the low protein counterparts (weighted mean difference: -0.71 μIU/ml, 95% CI -1.36 to -0.05, p = 0.03). Sensitivity analysis of high quality RCTs confirmed the data of the primary analyses, while exclusion of studies with diabetic subjects resulted in an additional benefit of high-protein diets with respect to a more marked increase in HDL-cholesterol. Conclusion: According to the present meta-analysis of long-term RCTs, high-protein diets exerted neither specific beneficial nor detrimental effects on outcome markers of obesity, cardiovascular disease or glycemic control. Thus, it seems premature to recommend high-protein diets in the management of overweight and obesity.