Abstract Background Secondary prevention in patients with acute coronary syndrome focuses on lowering low-density lipoprotein (LDL) cholesterol below 55 mg/dL. In all statin-naïve patients at high risk (LDL-cholesterol target <55 mg/dL), initiation of high-intensity statin monotherapy is recommended by ESC guidelines. Nonetheless, at one month, a significant proportion of patients do not reach their LDL-cholesterol target. Purpose The aim of this study was to compare lipid-lowering therapy with statin monotherapy versus statin with ezetimibe in secondary prevention in patients at high risk. Methods The current prospective study included 264 consecutive patients admitted with acute ST elevation myocardial infarction who underwent percutaneous coronary intervention. None of the patients had taken lipid-lowering drugs in the previous 12 months. Patients were randomly assigned to one of two treatment groups: Group 1 - rosuvastatin 40 mg (n= 144) and Group 2 - rosuvastatin 40 mg and ezetimibe 10 mg (n= 120). All patients' lipid profiles were assessed upon admission and after one month of lipid-lowering treatment. Results At baseline, no patient had LDL cholesterol level lower than 55 mg/dL. There was no significant difference in lipid profile at baseline between the two groups (all p > 0.05). No differences were observed between the two groups in terms of baseline LDL-cholesterol deviation from the target (103.4% versus 99.70%; p= 0.66). As expected, the combination therapy reduced LDL-cholesterol at one month significantly higher compared to high-dose statin monotherapy (-59.65% versus -37.54%; p< 0.0001). After one month of treatment, only 47.92% of patients in Group 1 reached the LDL-cholesterol target (<55 mg/dL) compared to 90.00% of the patients in Group 2 (p<0.0001; R.R.= 0.53). Conclusion(s) Our findings show that statin and ezetimibe combination therapy is more effective in reduction in LDL-cholesterol levels and reaching targets compared to statin monotherapy alone. In statin-naïve patients at high risk, early initiation of the statin and ezetimibe combination instead of statin monotherapy should be taken into account in secondary prevention, for an earlier reach of the LDL-cholesterol target and to reduce the overall cardiovascular risk.