Background & aims: Beyond cardiovascular disease protection, the health consequences of very low low-density lipoprotein-cholesterol (LDL-C) concentration remain a matter of debate. In primary hypobetalipoproteinemia (HBL), liver steatosis and cirrhosis have been occasionally reported. Here, we aimed to investigate the association between HBL and the risk of hepatic complications (cirrhosis complication and/or primary liver cancer) in the general population. Methods: A cohort study was conducted in the French population-based cohort CONSTANCES. Participants with primary HBL (LDL-C<5th percentile for age and sex, [HBL]) were compared with those with normal LDL-C concentrations (40th-60th percentile, [Control]). Participants on lipid-lowering therapies were excluded. For hepatic complications, follow-up events were compared by calculating the incidence density ratio (IDR). The same analyses were replicated in the UK Biobank (UKBB) cohort. Results: In the CONSTANCES and UKBB cohorts, 34,653 and 94,666 patients were analyzed, with median age of 45 and 56 years, mean LDL-C concentrations (HBL vs. Control) 71 vs. 128 mg/dL and 86 vs. 142 mg/dL, and mean follow-up of 5.0 and 11.5 years, respectively. The HBL group presented a higher incidence of hepatic complications than the control group: 0.32/1000 vs. 0.07/1000 person-years (IDR=4.50, 95%CI 1.91-10.6) in CONSTANCES, and 0.69/1000 vs. 0.21/1000 person-years (IDR=3.27, 95%CI 2.63-4.06) in UKBB. This risk proved to be independent of classic liver-disease risk factors (obesity, alcohol consumption, diabetes, viral hepatitis), including in a 5-year landmark analysis excluding early events. Sensitivity analyses replacing LDL-C by apoliprotein-B, or by individuals with genetically defined HBL, showed similar results. Conclusions: HBL is associated with a markedly increased risk of hepatic complications. HBL must be considered as a substantial independent risk factor for liver diseases which justifies specific prevention and screening.