This is the first population-based study to prospectively examine the association of circulating IGF-I and IGFBP-3 levels with development of liver cancer, doing so within a cohort of older middle-aged men who, although smokers, did not have a history of alcoholism, liver cirrhosis, or previous cancer, and who resided in a country that has low prevalence of HBV and HCV infections. Here, IGFBP3 is linked to liver cancer.