The objective of this study was to assess the influence of age and date of acquisition of hepatitis C virus (HCV) infection on the distribution of genotypes and the progression of fibrosis in HCV-infected patients who were born in Spain and had their habitual place of residence in this country. Genotypic analysis was performed in 375 patients in whom it was possible to establish the year of HCV infection because the mode of transmission was known (transfusion, injection drug use, blood donor, or epidemic outbreak). In 298 patients with liver biopsy, fibrosis stage was related to age at infection, duration of infection, alcohol consumption, and HCV genotype. HCV subtype 1b was almost exclusively detected among transfusion recipients, but the onset of intravenous drug addiction was associated with the introduction of HCV genotypes other than 1b among injecting users with subsequent spread to other exposure risk groups. Fibrosis progression was influenced by alcohol consumption, increased duration of infection, and older age at infection. In summary, spread of intravenous drug use determined HCV infection by genotypes other than 1b. The risk of fibrosis progression was influenced more by age at viral acquisition and alcohol consumption than by the infecting genotype.