Hepatitis C infection is a global health problem. Spontaneous viral clearance was observed in approximately 30% of individuals with acute infection. In the therapy using a combination of pegylated interferon-α and ribavirin, approximately 50% of chronic hepatitis C patients infected with high viremia of hepatitis C virus infection (HCV) genotype 1 reached a sustained viral response. These findings were strongly expected to reflect variations of the host genome. To reveal genetic effects against viral clearance or treatment response, four independent groups applied a genome-wide association study (GWAS) to HCV infection. These groups almost simultaneously reported a strong association of interleukin (IL)-28B polymorphisms with viral clearance or final decision of HCV therapy. The discovered single nucleotide polymorphisms (SNPs) also revealed the enigma that the viral clearance rate was dependent on ethnic type. The significant SNPs are useful for prediction prior to treatment because of the strong association with clinical outcome. In addition, the unexpected results revealed by GWAS could promote the development of a novel drug related to IL-28B. Herein, we present current understanding in regard to the relationship between host variations and clinical outcome of hepatitis C.