Our objective was to estimate HCV clinical burden over time in Italy. A national age-specific HCV prevalence in 1995 was obtained from studies conducted in general population samples and intravenous drug users. Age profile of new HCV infections and trend of incidence since 1985 were derived from a database of reported acute HCV infections. These incidence and prevalence data were used to estimate HCV burden from 1950 to 2030 by mathematical modelling. Different rates of HCV related liver disease progression were tested to assess the robustness of estimates. It is estimated that HCV had a major spread in Italy in 1945-1969. HCV RNA-positive subjects peaked around 1970; their prevalence in 2005 was 3.2%, 58% of them being >65 y of age. The number of individuals with HCV related cirrhosis and that of HCV liver related deaths peaked in 1980-1985. In 2005, they were approximately 230,000 (range 150,000-240,000, according to lower or higher disease progression rates) and approximately 7,000 (range 2200-12,300), respectively: both will be halved by 2025. In conclusion, unlike other industrialized countries, the burden of clinically relevant HCV-positive cases in Italy is already on the decline and will further reduce in the future. This is due to differences in the age-specific prevalence, most of HCV-positive Italians currently being >65 y of age.