Aggressive low-density lipoprotein (LDL) cholesterol-lowering therapy is important for high-risk patients. However, sparse data exist on the impact of combined aggressive LDL cholesterol-lowering therapy in familial hypercholesterolemia (FH), particularly on side effects to changes in plasma coenzyme Q10 and proprotein convertase subtilisin/kexin type 9 levels. We enrolled 17 Japanese patients with heterozygous FH (12 men, 63.9 ± 7.4 years old) with single LDL receptor gene mutations in a prospective open randomized study. Permitted maximum doses of rosuvastatin (20 mg/day), ezetimibe (10 mg/day), and granulated colestimide (3.62 g/day) were introduced sequentially. Serum levels of LDL cholesterol decreased significantly by −66.4% (p <0.001) and 44% of participants achieved LDL cholesterol levels <100 mg/dl. There were no serious side effects or abnormal laboratory data that would have required the protocol to have been terminated except for 1 patient with myalgia. Coadministration of ezetimibe and granulated colestimide further lowered serum LDL cholesterol more than rosuvastatin alone without changing plasma coenzyme Q10 and proprotein convertase subtilisin/kexin type 9 levels. In conclusion, adequate introduction of this aggressive cholesterol-lowering regimen can improve the lipid profile of FH.