Background: A statin alone or non-statins as add-ons have been introduced to intensive low-density lipoprotein cholesterol (LDL-C) -lowering therapy in patients at risk for high cardiovascular disease (CVD). The purpose of this study was to evaluate the effectiveness and safety of different rosuvastatin-based regimens for patients at high risk. Methods: Three hundred patients at high CVD risk were randomly assigned to the statin group (rosuvastatin, 20 mg/d), statin_EZ group (statin 10 mg/d + ezetimibe 10 mg/d), statin_pcsk group (statin 10 mg/d + alirocumab 75 mg/2 weeks) or combine3 group (statin 10 mg/d + ezetimibe 10 mg/d + alirocumab 75 mg/2 weeks). The primary outcome measure was cholesterol levels after 24 weeks of follow-up. Secondary outcomes included safety markers and the proportion of patients achieving the 70 mg/dL (1.8 mmol/L) target for LDL-C. A logistic regression model was performed to explore the factors affecting lipid target achievement. Results: The total cholesterol (TC) and LDL-C levels in the four groups after treatment were significantly lower than those before treatment. TC and LDL-C levels after treatment were significantly different among the four groups (p 0.05). The levels in both the combine3 and statin_pcsk9 groups were significantly lower than those in the statin and statin_EZ groups (p 0.05), but there was no significant difference between the combine3 and statin_pcsk9 groups. Fifty-one participants (69%) in the statin_pcsk9 group and 56 participants (78%) in the combine3 group achieved the target. Body mass index (BMI) and hypertensive status were related to LDL-C target achievement. The incidence of adverse events in the four groups was low. Conclusions: The combination of a statin and a PCSK9 inhibitor was safe and more effective for the treatment of high-risk CVD patients, while the addition of ezetimibe was unable to significantly lower lipid levels any further. The rate of achieving the target was higher in patients with hypertension and a low BMI. Clinical Trial Registration: Chinese Clinical Trial Registry, Identifier: ChiCTR2200058389, Date of Registration: 2022-04-08.