Objective: Diabetes and hypercholesterolemia is well-known risk factors for cardiovascular disease. The apolipoprotein B/A1 (apoB/A1) ratio is an effective predictor of incident cardiovascular disease. Statin and ezetimibe combination therapy have been reported additional cardioprotective effects over statin monotherapy. We aimed to assess the efficacy and safety of combination treatment of rosuvastatin with ezetimibe in patients with diabetes and hypercholesterolemia. Methods: In this multicenter, randomized, open-label study, we randomly assigned patients (total, n = 140) with diabetes and hypercholesterolemia to receive rosuvastatin/ezetimibe (5 mg/10 mg, n = 70) combination therapy or rosuvastatin (10 mg, n = 70) monotherapy for 8 weeks. The primary endpoint was the percentage change in apoB/A1 ratio from baseline to week 8. Results: After the 8-week treatment, the percentage change in apoB/A1 ratio reduction were significantly decreased in the rosuvastatin/ezetimibe group than in the rosuvastatin group (-46.14 ± 1.58% vs. -41.30 ± 1.58%, P = 0.03). In addition, the percentage of patients achieving ≥ 50% reduction in LDL cholesterol was 76.5% (52/68) in the rosuvastatin/ezetimibe group and 47.1% (32/68) in the rosuvastatin group (P = 0.0004), and the percentage of patients achieving comprehensive lipid target without drop-out due to adverse events was 73.5% (50/68) in the rosuvastatin/ezetimibe group and 45.6% (31/68) in the rosuvastatin group (P = 0.0009). Moreover, the reduction from baseline to week 8 of total cholesterol, non-HDL cholesterol, LDL cholesterol, and apo B were greater in the rosuvastatin/ezetimibe group than in the rosuvastatin group. Both treatments were generally well tolerated, and there were no statistically significant differences in drug-related adverse events. Conclusion: A 8-week combination therapy of rosuvastatin and ezetimibe showed a significant reduction in apoB/A1 ratio, a predictor of future cardiovascular disease, without increasing adverse event compared to rosuvastatin monotherapy in the patient with diabetes and hypercholesterolemia.