Efforts to expand the donor organ pool for transplantation are ongoing, including transplantation of HCV-positive organs. Pre-emptive administration of pangenotypic direct-acting antiviral (DAA) therapy to prevent the development of chronic HCV infection in uninfected recipients of HCV-positive donor hearts was investigated in a proof-of-concept study. 20 patients underwent transplantation with a viraemic donor heart (according to nucleic acid testing) and received pre-emptive oral glecaprevir–pibrentasvir before the operation and an 8-week course after transplantation. 5 additional patients received HCV antibody-positive donor hearts without detectable circulating HCV RNA, but did not develop viraemia and so did not receive DAA therapy. DAAs were well-tolerated, rapidly suppressed HCV (median time to clearance of 3.5 days) and prevented chronic HCV infection (sustained virologic response at 12 weeks). Patient and allograft survival were 100% at a median follow-up of 10.7 months (range 6.5–18.0).