Background: The existing literature regarding smoking and alcohol consumption and risk of gastrointestinal bleeding (GIB) is sparse and conflicting. In an attempt to study modifiable risk factors of GIB, we assessed the risk of GIB associated with smoking and alcohol consumption in a large prospective cohort of men. Methods: We studied 51,529 men in the Health Professional follow-up Study (HPFS) who were aged 40-75 years at baseline in 1986. We identified men with GIB requiring hospitalization and/or blood transfusion based on their responses to biennial questionnaires from 2006-2012 and reviewed medical records to validate self-report. Information about smoking and alcohol consumption was updated every two and four years, respectively. We used Cox proportional hazards regression to calculate the relative risks (RR) and 95% confidence intervals (CI) adjusting for age, study year, body mass index, physical activity, regular aspirin and nonsteroidal anti-inflammatory drug use, and alcohol/smoking. Results: We documented 311 episodes of GIB during a 26-year follow up period. After adjustments for other potential risk factors, individuals who consumed >15 g/day of alcohol had a multivariate RR of 1.65 (95% CI, 1.10-2.47; p for linear trend 0.004) when compared with men who did not consume alcohol. Intake of > 15 g/day of alcohol appeared to be primarily related to upper GIB (multivariable RR 1.74; 95% CI, 0.98-3.08; p for linear trend 0.007). Risk of GIB increased linearly with amount of liquor consumed (p for linear trend 15 g/day of alcohol was significantly associated with peptic ulcer disease (multivariable RR 1.85; 95% CI, 0.97-3.54; p for linear trend 0.02), but not esophagitis/gastritis/duodentitis, or diverticular bleeding. There were few cases of bleeding due to portal hypertension (n=4). Current and past smokers did not appear to have increased risk of GIB when compared to those who never smoked (multivariable RR 0.89; 95% CI, 0.45-1.76 and 1.12, 95% CI 0.88-1.41, respectively). We also did not find a significant association between pack years of smoking and risk of GIB (multivariable RR 1.01; 95% CI, 0.63-1.62 when comparing men with at least 45 pack-years of exposure to never smokers). Conclusions: In this large prospective study, alcohol consumption, but not smoking, was associated with an increased risk of GIB. Associations were most notable for upper GI bleeding associated with intake of liquor.