Background Patients with diabetes mellitus (DM) and metabolic syndrome (MS) are at increased risk of developing coronary heart disease. Objective To compare the effects of ezetimibe/simvastatin (E/S) combination therapy, atorvastatin, and rosuvastatin in patients with DM, MS without DM, or neither disease. Methods Subgroup analysis of data from two 6-week, randomized, double-blind trials comparing E/S 10/10, 10/20, 10/40, or 10/80 mg with either atorvastatin 10, 20, 40, or 80 mg (Study 1), or rosuvastatin 10, 20, or 40 mg (Study 2). Treatments were compared by pooling across all doses for effects on low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), total cholesterol (TC), non–HDL-C, apolipoprotein B (ApoB), LDL-C:HDL-C, TC:HDL-C, and LDL-C goal attainment. Results E/S provided greater improvements than atorvastatin or rosuvastatin in LDL-C, TC, HDL-C (vs atorvastatin only), non–HDL-C, LDL-C:HDL-C, TC:HDL-C, and ApoB in all disease subgroups. There were no interactions of treatment by disease subgroup for these parameters, indicating a consistent treatment difference favoring E/S effect across the disease subgroups. A greater percentage of patients receiving E/S than atorvastatin or rosuvastatin attained their individual National Cholesterol Education Program Adult Treatment Panel III LDL-C goals, LDL-C <100 mg/dL, LDL-C <70 mg/dL, and non–HDL-C goals regardless of subgroup. All treatments were well-tolerated, with generally similar adverse experience rates. Conclusions Overall, E/S generally provided greater efficacy than either atorvastatin or rosuvastatin that was consistent across the subgroups of patients with DM, MS, or neither, in agreement with the results from the full study cohorts.