Only three Japanese prospective studies have suggested an inverse association between coffee drinking and liver cancer risk. No prospective studies on the association between serum gamma-glutamyltransferase (GGT) and liver cancer risk have been reported. We aimed to determine the single and joint associations of coffee consumption and serum GGT with the risk of primary liver cancer. Study cohorts included 60,323 Finnish participants who were 25-74 years of age and free of any cancer at baseline. During a median follow-up period of 19.3 years (interquartile range: 9.3-29.2 years), 128 participants were diagnosed with an incident liver cancer. The multivariable-adjusted (age, sex, alcohol consumption, education, smoking, diabetes and chronic liver disease at baseline and during follow-up, and body mass index) hazards ratios of liver cancer in participants who drank 0-1, 2-3, 4-5, 6-7, and >8 cups of coffee daily were 1.00, 0.66, 0.44, 0.38, and 0.32 (P for trend β«Ψβ¬ 0.003), respectively. Further adjustment for serum GGT in subgroup analysis affected the results only slightly. The multivariable-adjusted and coffee-adjusted hazard ratio of liver cancer for the highest versus the lowest quartile of serum GGT was 3.13 (95% confidence interval β«Ψβ¬ 1.22-8.07). The multivariable-adjusted inverse association between coffee consumption and liver cancer risk persisted when stratified by baseline factors: age more/less than 50 years, current smoker/never smoked/ever smoked, alcohol drinker/never drinker, obese/nonobese, and the highest/lowest three quartiles of serum GGT. A combination of very low coffee consumption and high level of serum GGT was associated with nearly nine-fold increased risk. Conclusion: Coffee drinking has an inverse and graded association with the risk of liver cancer. High serum GGT is associated with an increased risk of liver cancer. (HEPATOLOGY 2008;48:129-136.) See Editorial on Page 7 L iver cancer is the third most common cause of death from cancer worldwide. 1 The incidence rate of liver cancer is high in western and central Africa, and southeastern and eastern Asia, low in most developed countries (except for Japan), and between in some southern European countries. 1 Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections have been identified as causative factors in more than 75% of cases worldwide and 85% of cases in less-developed countries. 1,2 However, the prevalence of HBV and HCV infections in most developed countries, except for Japan, Italy, and Greece, is low. 3,4 Coffee is one of the most consumed beverages in the world. In last several years, three Japanese prospective studies have suggested an inverse association between cof-