Abstract Background Recent studies in chronic hepatitis C patients have shown that rs368234815 polymorphism nearby IL28B is a better predictor of response to antiviral treatment with pegylated interferon and ribavirin than IL28B polymorphisms (rs12979860 and rs8099917). Its effect could be related to interferon lambda 4 (IFNL4), a protein which seems to confer some paradoxical disadvantages in hepatitis C virus (HCV) immune response. Objectives To assess the role of IFNL4 rs368234815 polymorphism on the response to antiviral treatment after liver transplantation (LT). Study design IFNL4 and IL28B polymorphisms were genotyped in 86 HCV-infected LT recipients and in their donors; all patients had undergone antiviral treatment with pegylated interferon and ribavirin after LT. Results IFNL4 polymorphism strongly correlated with IL28B ones (p<0.001). The favorable IFNL4 genotype (TT/TT) was significantly more frequent among donors than recipients (60% donors vs. 22% recipients, p<0.001). Recipient TT/TT genotype was associated with a higher sustained virological response rate after LT (p=0.024). Nevertheless, the highest sustained virological response frequency was found when both donors and recipients had favorable genotypes (73% vs. 25%, p=0.002), suggesting a role for donor genotype. Conclusions Our study demonstrates that IFNL4 rs368234815 polymorphism is an important predictor of response to antiviral treatment in the LT setting. These findings warrant further studies on IFNL4 role in immune response against HCV.