Background/Aims: The role of coffee in the development of hepatocellular carci noma (HCC) is debated. The aim of this study was to investigate the role of coff ee in HCC, taking the main risk factors into account. Methods: A hospital-based case-control study was conducted in an area of northern Italy.We recruited 250 HCC cases and 500 controls hospitalized for any reasons other than neoplasms, a nd liver and alcohol-related diseases. Subjects were interviewed on their lifet ime history of coffee consumption using a standardized questionnaire. Results:Co ffee consumption in the decade before the interview was associated with a decrea sing risk of HCC with a clear dose-effect relation. With respect to non-drinki ng subjects, the odds ratios (ORs) were: 0.8, (95%CI 0.4-1.3) for 1-2 cups/da y,0.4 (95%CI 0.2-0.8) for 3-4 cups/day and 0.3 (95%CI 0.1-0.7) for 5 or mor e cups/day. The ORs for HCC decreased for drinking >2, compared to 0-2 cups/day of coffee, for an alcohol intake >80 g/day (OR from 5.7 to 3.3), for presence o f hepatitis B virus infection (OR from 16.4 to 7.3) or hepatitis C virus infecti on (OR from 38.2 to 9.0). Conclusions: Coffee drinking was inversely associated with HCC regardless of its aetiology.