Hypercholesterolemia is characterized by high plasma LDL cholesterol and often caused by genetic mutations in LDL receptor (LDLR), APOB, or proprotein convertase subtilisin/kexin type 9 (PCSK9). However, a substantial proportion of hypercholesterolemic subjects do not have any mutations in these canonical genes, leaving the underlying pathobiology to be determined. In this study, we investigated to determine whether combining plasma metabolomics with genetic information increases insight in the biology of hypercholesterolemia. For this proof of concept study, we combined plasma metabolites from 119 hypercholesterolemic females with genetic information on the LDL canonical genes. Using hierarchical clustering, we identified four subtypes of hypercholesterolemia, which could be distinguished along two axes represented by triglyceride and large LDL particle concentration. Subjects with mutations in LDLR or APOB preferentially clustered together, suggesting that patients with defects in the LDLR pathway show a distinctive metabolomics profile. In conclusion, we show the potential of using metabolomics to segregate hypercholesterolemic subjects into different clusters, which may help in targeting genetic analysis.