Previously, RNA transcripts of cDNA clones of hepatitis C virus (HCV) genotypes 1a (H77, HCV-1 and HC-TN), 1b (HC-J4, Con1, and HCV-N) and 2a (HC-J6 and JFH1) were found to be infectious in chimpanzees. However, only JFH1 was infectious in human hepatoma Huh7 cells. We performed genetic analysis of HCV genotype 3a (S52) and 4a (ED43) prototype strains, and generated full-length consensus cDNA clones (pS52 and pED43). Transfection of Huh7.5 cells with RNA transcripts of these clones did not yield HCV Core expressing cells. However, intrahepatic transfection of chimpanzees resulted in robust infection with peak HCV RNA titers of approximately 5.5 log10 IU/mL. Genomic consensus sequences recovered from serum at time points of peak viral titers were identical to the parental plasmids. Both chimpanzees developed acute hepatitis with elevated liver enzymes and significant necro-inflammatory liver changes coinciding with detection of interferon-gamma secreting, intrahepatic T cells. However, onset and broadness of intrahepatic T-cell responses varied greatly in the two animals, with an early (week 4) multi-specific response in the ED43 infected animal (three weeks before first evidence of viral control), and a late (week 11) response with limited breadth in the S52 infected animal (without evidence of viral control). Autologous serum neutralizing antibodies were not detected during the acute infection in either animal. Both animals became persistently infected. In conclusion, we generated fully functional infectious cDNA clones of HCV genotypes 3a and 4a. Proof of functionality of all genes might further the development of recombinant cell culture systems for these important genotypes.