Abstract Context Angiopoietin-like 3 (ANGPTL3) deficiency in plasma due to loss-of-function gene mutations results in familial combined hypobetalipoproteinemia type 2 (FHBL2) in homozygotes. However, the lipid phenotype in heterozygotes is much milder and does not appear to relate directly to ANGPTL3 levels. Furthermore, the low-density lipoprotein (LDL) phenotype in carriers of ANGPTL3 mutations is unexplained. Objective To determine whether reduction below a critical threshold in plasma ANGPTL3 levels is a determinant of lipoprotein metabolism in FHBL2, and to determine whether proprotein convertase subtilisin kexin type 9 (PCSK9) is involved in determining low LDL levels in this condition. Design We studied subjects from 19 families with ANGPTL3 mutations and subjects with familial combined hypobetalipoproteinemia type 1 (FHBL1) due to truncated apolipoprotein B (apoB) species. Results First, total cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, and HDL and LDL particle concentration correlated with plasma ANGPTL3 levels but only when the latter was <25% of normal (<60 ng/dL). Second, the very low-density lipoprotein particle concentration correlated strongly with plasma ANGPTL3 when the latter was <58% of normal. Third, both FHBL1 and FHBL2 subjects showed low levels of mature and LDL-bound PCSK9 and higher levels of its furin-cleaved form. Finally, LDL-bound PCSK9 is protected from cleavage by furin and binds to the LDL receptor more strongly than apoB-free PCSK9. Conclusions Our results suggest that the hypolipidemic effects of ANGPTL3 mutations in FHBL2 are dependent on a threshold of plasma ANGPTL3 levels, with differential effects on various lipoprotein particles. The increased inactivation of PCSK9 by furin in FHBL1 and FHBL2 is likely to cause increased LDL clearance and suggests novel therapeutic avenues.