This study was designed to investigate the role of killer immunoglobulin-like receptor (KIR) genes in the outcome of hepatitis C virus (HCV) infection. In patients who cleared the virus (HCV RNA−) we found a decrease of 2DL2 (P= 0.04), and 2DS2 (P= 0.014) accompanied by an increase of 2DS5 (P= 0.04). Those RNA+ patients with elevated levels of hepatic transaminases (HCV RNA+ elevated alanine aminotransferase) showed an increased frequency of 2DS3 (P= 0.018). Additionally, in cirrhotic patients we found an increased frequency of individuals having two copies of 3DS1 and HLA-Bw4 (P= 0.016). We conclude that higher natural killer cytotoxicity might be associated with a worse progression of the HCV infection.