Hepatitis C virus (HCV) co-opts the very low-density lipoprotein (VLDL) pathway for morphogenesis, maturation, and secretion, and circulates as lipoviroparticles (LVPs). We investigated the functions and underlying mechanisms of the lipid-associated transmembrane 6 superfamily 2 (TM6SF2) protein in modulating LVP formation and the HCV life cycle.