End stage liver disease caused by chronic infection with the hepatitis C virus (HCV) is a leading indication for liver transplantation, yet outcomes are poor since the liver graft is rapidly re-infected by HCV. Antibodies against the essential HCV receptor CD81 have been shown to inhibit HCV cell entry in vitro and in vivo and may represent an attractive treatment option. However, several CD81 variants exist at low levels in human populations. We aimed to investigate to what extent these variants function as HCV receptors and would be amenable to therapeutic interventions with CD81 antibodies. We used lentiviral expression to introduce wildtype or variant CD81 in the CD81(low) Lunet N4 cell line. HCV replication cycle steps and neutralization by CD81 antibodies were then investigated using full length HCV reporter viruses (HCVcc) as well as HCV pseudoparticles (HCVpp). We found that all tested CD81 variants support cell entry by HCVpp and HCVcc with an efficiency similar to wildtype CD81. Other replication cycle steps, namely intracellular RNA replication and release of new particles, were also unaffected by the presence of CD81 variants. Importantly, four neutralizing antibodies directed against the CD81 LEL (5A6, JS81, 1D6 and 1.3.3.22) retained their ability to inhibit HCV infection when wildtype CD81 on target cells was replaced with any of the CD81 variants. These data indicate that CD81 variants that exist in the human population are fully functional as HCV receptors and their presence would not diminish the efficacy of therapeutic regimens that include CD81-antibodies.