Raised low-density lipoprotein (LDL) cholesterol is believed to predispose to development of atherosclerosis and coronary heart disease. Increased plasma LDL concentrations and premature coronary heart disease are present in familial hypercholesterolemia (FH), and the enzyme lipoprotein lipase (LPL) seems to have a key role in production of LDL. We describe a unique French Canadian individual who is both heterozygous for FH and homozygous for LPL deficiency (FH/LPL). In this patient, LDL cholesterol was strikingly low compared with both his FH (0.65 vs 5.84 mmol/L) and normolipidaemic (2.77 mmol/L) age-matched relatives despite the defect of LDL-receptor-mediated removal. No LDL peak was present in the cholesterol profile of the FH/LPL-deficient subject, as determined by density-gradient ultracentrifugation. Our results suggest that most LDL particles, in vivo, originate from triglyceride-rich lipoproteins, that LPL plays a vital part in this process, and that absence of LPL activity protects FH subjects against the increase in LDL cholesterol.