Antihyperlipidemic agents such as 3-hydroxymethyglutaryl-coenzyme A reductase inhibitors and cholesterol transporter inhibitors are used in coronary heart disease. However, controversy remains over the pharmacologic effects and safety of these drugs, especially when used in combination therapies. This retrospective study evaluated the therapeutic effect and safety of simvastatin 20 mg and ezetimibe 10 mg combination therapy compared to simvastatin 20 mg or ezetimibe 10 mg monotherapy in Korean patients according to gender, age, baseline low-density lipoprotein cholesterol, and cardiovascular risk factors. We observed significant differences among patient subgroups. Simvastatin and ezetimibe monotherapies and combination therapy reduced low-density lipoprotein cholesterol levels by 27.6%, 10.1%, and 36.8% (p < 0.001) and total cholesterol levels by 17.5%, 9.2%, and 25.3% (p < 0.001), respectively. Both monotherapy and combination therapy groups had similar incidences of all types of adverse events. However, one case of rhabdomyolysis was observed in the combination therapy group. These results suggest that, compared to monotherapy, combination therapy has an additive effect that is not influenced by risk factors. Despite the low incidence of adverse events, caution is required when using these drugs, especially in the context of musculoskeletal side effects.