Background:The increasing prevalence of diabetes may contribute to the rising incidence of hepatocellular carcinoma (HCC) in the US and other developed countries where HCC incidence is relatively low. Data from prospective studies on diabetes and risk of HCC in at-risk populations due to high prevalence of viral hepatitis in southeast Asia are sparse.Methods:The Singapore Chinese Health Study is a prospective cohort of 63 257 middle-aged and older Chinese men and women enrolled in 1993–1998. Besides an in-person interview administered to all participants at baseline, testing of serologic markers of hepatitis B or C infections were performed on a subset of cohort subjects. After a mean follow-up of 14 years, 499 cohort participants developed HCC.Results:A history of diabetes at baseline was associated with a hazard ratio of 2.14 (95% confidence interval, 1.69–2.71). This statistically significant association was comparable in magnitude between men and women, and remained equally strong across strata of subjects defined by the number of years between their first clinical diagnosis of diabetes and time of enrolment in this cohort. Within a nested case-control set of cohort subjects tested for serological markers of hepatitis B or C infections, the diabetes–HCC association was found to be present mainly among those devoid of any markers.Conclusion:A history of diabetes at baseline is highly associated with non-viral HCC. Future studies are warranted to elucidate the biological mechanism underpinning the role of diabetes in nonviral-related hepatocarcinogenesis.