The risk of developing liver cancer in hepatitis B virus (HBV) carriers differs across geographical areas, suggesting that exposure to other risk factors may contribute to HBV-linked cancer risk. Our study estimates the mortality due to liver disease and the role of other risk factors in a Spanish HBV cohort. 2,352 hepatitis B surface antigen (HBsAg)-positive and 15,504 HBsAg-negative subjects were identified among blood donors during 1972–1985 and were followed until December 2000 through the Mortality Registry. Clinical examination and an epidemiological questionnaire were performed on 1,000 HBsAg-positive survivors during 1994–1996. In subjects deceased from liver disease, medical records were revised and relatives were interviewed. A nested case-control analysis was conducted comparing both groups. In HBsAg-positive men, an excess mortality from liver cancer [standardized mortality ratio (SMR): 14.1; 7.7–23.6], cirrhosis (SMR: 10.5; 7.0–15.1), haematological neoplasms (SMR: 3.2; 1.2–6.9) and AIDS was detected (SMR: 5.5; 2.2–11.4). In women, an excess was found for cirrhosis (SMR: 7.2; 1.4–21.1). Progression factors to liver disease were alcohol intake [odds ratio (OR): 6.3; 3.1–12.8], diabetes (OR: 3.6; 1.3–9.6), HBV replication (OR: 50.0; 14.9–167.3) and hepatitis C virus (HCV) infection (OR: 27.4; 7.1–107.7). In conclusion, in Spain after 20 years of follow-up, chronic HBV exposure appears as a major risk factor for liver cancer among men and for cirrhosis in both sexes. The risk of death from liver disease among HBV carriers with the presence of HBV replication, HCV, alcohol consumption and diabetes was significantly increased and suggests synergism among these exposures and HBV. Mortality from haematological neoplasms was detected and could be associated to HIV coinfection. These results support screening and adequate follow-up among HBsAg-positive subjects at high risk to develop liver disease, particularly when these risk cofactors are present. © 2006 Wiley-Liss, Inc.