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Background: Japan has the highest incidence rate of primary liver cancer attributed to chronic hepatitis C virus (HCV) infection among developed countries. Molecular clock analysis of HCV sequences revealed that the spread of HCV took place earlier in Japan than in other countries. This might influence recent temporal trends in hepatocellular carcinoma (HCC) incidence., Objective: To characterize the contribution of HCV-related hepatocellular carcinoma (HCC) to recent changes in HCC incidence in Osaka, Japan., Design: Population-based survey., Setting: Osaka Cancer Registry and 10 hospitals in Osaka., Participants: 63,862 patients with HCC that was diagnosed between 1981 and 2003 in Osaka Prefecture, including 5253 HCV-seropositive patients with HCC that was diagnosed between 1990 and 2003 at 10 hospitals., Measurements: Incidence of HCC and estimated incidence rate of HCV-related HCC, measured by multiplying the prevalence of anti-HCV by the corresponding HCC incidence rate., Results: Between 1981 and 2003, peak incidence of HCC among men age 50 to 59 years, 60 to 69 years, and 70 to 79 years occurred in 1986, 1995, and 2000, respectively, with marked downward trends thereafter (average annual change, -7.9, -22.3, and -12.4 per 100,000 persons, respectively). Similar trends were observed in women. Estimated sex- and age-specific incidence of HCV-related HCC (per 100,000 persons) decreased from 255 to 92 cases at the maximum in men age 60 to 69 years and from 61 to 34 cases in women age 60 to 69 years, whereas estimated incidence of non-HCV-related HCC did not change between 1990 and 2003., Limitation: Infection was determined only by HCV seropositivity., Conclusion: The incidence of HCC in Osaka started to decrease by 2000, mainly because of decreased HCV-related HCC.