BackgroundUncertainties still existed about the effect of high-quality protein supplementation on cardiovascular disease (CVD) risk factors, although high-quality proteins such as soy and milk proteins have proposed to be beneficial for cardiometabolic health. MethodsA systematic search in PubMed, Web of Science, Cochrane Library, Scopus, and Embase was conducted to quantify the impact of high-quality protein on CVD risk factors. Results63 RCTs on 4 types of high-quality protein including soy protein, milk protein, whey, and casein were evaluated. Soy protein supplementation decreased systolic blood pressure (SBP, -1.42 [-2.68, -0.17] mmHg), total cholesterol (TC, -0.18 [-0.30, -0.07] mmol/L), and low-density lipoprotein cholesterol (LDL-C, -0.16 [-0.27, -0.05] mmol/L). Milk protein supplementation decreased SBP (-2.30 [-3.45, -1.15] mmHg) and total cholesterol (-0.27 [-0.51, -0.03] mmol/L). Whey supplementation decreased SBP (-2.20 [-3.89, -0.51] mmHg), diastolic blood pressure (DBP, -1.07 [-1.98, -0.16] mmHg), triglycerides (-0.10 [-0.17, -0.03] mmol/L), TC (-0.18 [-0.35, -0.01] mmol/L), LDL-C (-0.09 [-0.16, -0.01] mmol/L) and fasting blood insulin (FBI, -2.02 [-3.75, -0.29] pmol/L). Casein supplementation decreased SBP (-4.10 [-8.05, -0.14] mmHg). In the pooled analysis of four high-quality proteins, differential effects were seen in individuals with different health status. In hypertensive individuals, high-quality proteins decreased both SBP (-2.69 [-3.50, -1.87] mmHg) and DBP (-1.34 [-2.09, -0.60] mmHg). In overweight/obese individuals, high-quality proteins improved SBP (-1.40 [-2.22, -0.59] mmHg), DBP (-2.59 [-3.20, -1.98] mmHg), triglycerides (-0.09 [-0.15, -0.02] mmol/L), TC (-0.14 [-0.22, -0.05] mmol/L), LDL-C (-0.12 [-0.16, -0.07] mmol/L), and HDL-C levels (0.02 [0.01, 0.04] mmol/L). According to the benefits on CVD risks factors, whey ranked top for improving cardiometabolic health in hypertensive or overweight/obese individuals. ConclusionOur study supports a beneficial role of high-quality protein supplementation to reduce CVD risk factors. Further studies are still warranted to investigate the effects of different high-quality proteins on CVD risks in individuals with cardiometabolic disorders.