Objectives <p>Observational studies suggest a potential link between Hepatitis C virus (HCV) infection and extrahepatic cancers, but the causal relationship remains unclear.</p> Methods <p>We applied a two-sample Mendelian randomization (MR) approach to evaluate the causal relationships between HCV infection and various extrahepatic cancers. A two-step MR was used to identify potential mediators, followed by colocalization analysis to identify HCV-associated susceptibility genes (HSGs). A pan-cancer analysis using TCGA data was conducted, and a prognostic model based on HSGs was developed using least absolute shrinkage and selection operator (LASSO) regression and Cox models. Genetic risk score (GRS) analysis from the UK Biobank validated our findings.</p> Results <p>We identified a causal link between genetic susceptibility to HCV infection and kidney cancer, both in univariable and multivariable MR analyses. The two-step MR identified five mediators in the causal pathway. <i>IRF5</i> was highlighted as a key HSG in both the colocalization and pan-cancer analyses. Our prognostic model incorporating three HSGs predicted overall survival (OS) in kidney cancer patients. GRS analysis confirmed the association.</p> Conclusions <p>The present study provides evidence supporting a causal link between HCV infection and the development of kidney cancer.</p>