BACKGROUND Inhibitors of proprotein convertase subtilisin kexin 9 are indicated in Canada for treatment of patients with familial hypercholesterolemia (FH). Classically, FH is considered to be a monogenic condition caused by rare pathogenic mutations; however, some patients have hypercholesterolemia on a polygenic basis. Whether the effect of proprotein convertase subtilisin kexin 9 inhibitor treatment differs between patients with monogenic hypercholesterolemia and patients with polygenic hypercholesterolemia is unclear. METHODS We performed retrospective chart reviews on patients treated with evolocumab 140 mg subcutaneously biweekly from the Lipid Genetics Clinic, London Health Sciences Centre. Evolocumab-treated patients with hypercholesterolemia were grouped into monogenic or polygenic categories on the basis of their genotype determined by targeted next-generation sequencing. Absolute and relative changes in low-density lipoprotein cholesterol (LDL-C) levels before and after evolocumab treatment were studied. RESULTS In 32 patients with monogenic heterozygous FH and 7 patients with polygenic hypercholesterolemia treated with evolocumab, absolute incremental reductions in LDL-C were 2.94 ± 1.22 mmol/L and 3.15 ± 0.90 mmol/L, respectively (P = not significant), whereas percent reductions in LDL-C were 63.9% ± 16.0% and 67.7% ± 20.7%, respectively (P = not significant). CONCLUSIONS Although the sample size is small, the findings suggest comparable biochemical responsiveness to evolocumab in both monogenic (heterozygous) and polygenic hypercholesterolemia.