Smoking is the world's leading cause of premature mortality responsible for an estimated 5 million deaths each year. Although the negative health implications of cigarette smoking in the nontransplant setting are well recognized, the effect on patient and graft survival post liver transplantation remains unclear. The aim of this study was therefore to assess the influence of smoking on morbidity and mortality following liver transplantation. We performed a retrospective single-center case-note study of 136 consecutive patients who underwent elective liver transplantation between January 1, 1996 and December 31, 2000. Patients were defined as active smokers (23%), exsmokers (18%), or life-long nonsmokers (58%) on the basis of documentation at the time of transplant assessment. Active smoking was associated with increased all-cause mortality post transplant, with estimated 1-, 5-, and 10-year survival of 94%, 68%, and 54%, respectively, versus 94%, 83%, and 77% for nonsmokers (P = 0.04). A multivariate Cox proportional hazards model identified smoking as an independent predictor of death (hazard ratio 2.23, 95% confidence interval 1.08-4.61, P = 0.03). Active smokers demonstrated increased cardiovascular-specific mortality (P = 0.01) and sepsis-specific mortality (P = 0.02) but not malignancy-related mortality (P = 0.61) and had graft survival similar to that of nonsmokers (P = 0.88). Exsmokers did not have an increased risk of death (P = 0.134). In conclusion, active smokers at time of assessment have increased mortality post liver transplantation, which is non-graft-related and appears to be a result of increased cardiovascular-related and sepsis-related death. Prospective studies are required to assess the impact of smoking cessation on long-term outcome.