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Hepatitis C virus (HCV) is a blood-borne, liver tropic positive single stranded RNA virus. 70-80% of the 3-4 million yearly infections become chronic leading to increased risk of liver cirrhosis and liver cancer, and 2-3% of the total world population are estimated to be chronically infected. There is no prophylactic vaccine against HCV, but the virus can be treated with a combination of direct-acting antivirals (DAAs). However, resistance mutations towards specific DAA are known to occur. RNA recombination is a mechanism, by which two independent RNA molecules are combined to make up a new molecule partially derived from each of the parental molecules. Recombinant forms have been observed for a number of viruses, including HCV, constituting an evolutionary shortcut. In this study, cell culture co-transfection with the non-viable J6CF and JFH1ΔE1E2 genomes demonstrated hepatitis C virus RNA recombination. In total, five different recombinant viruses were characterized and four of these were heterologous recombinants, whereas one was homologous. Three recombinants with low fitness co-infected a single culture for several weeks. Except for one of the highly attenuated recombinants, the position of the recombination junction ensured a monophyletic NS3-NS5B region. Next, RNA recombination was investigated as a potential escape mechanism from combination therapy putatively combining variants with escape mutations to individual inhibitors. The recombinant virus strains J6-18 and m15-J4NS5A were selected due to reciprocal resistance to the NS5A and miR-122 inhibitors, daclatasvir and miravirsen, respectively. Cell culture treatment conditions were established and cells were co-transfected with the two genomes and treated with combination therapy. However, no resistant recombinants were observed, potentially due to non-viability of potential recombinants, thereby failing to provide proof-of-concept for recombination as escape mechanism in the studied setup. Furt