Moderate alcohol consumption is associated with lower levels of several coagulation factors. It is an established protective factor for cardiovascular disease; however, the effect on venous thrombosis is unknown. In a large population-based case-control study, we evaluated the association between alcohol consumption and the risk of venous thrombosis. The MEGA study included consecutive patients with a first venous thrombosis between March 1999 and September 2004 from six anticoagulation clinics in the Netherlands. Partners of patients were asked to participate, and additional controls were recruited using a random digit dialling method. All participants completed a standardized questionnaire, and blood samples were collected. A total of 4,423 patients and 5,235 controls were included in the analyses. Alcohol consumption was associated with a reduced risk of venous thrombosis, with 2-4 glasses per day resulting in the largest beneficial effect (odds ratio [OR] 0.67, 95% confidence interval [CI95] 0.58-0.77) compared to abstainers. The effect was more pronounced in women (OR 0.66, CI95 0.53-0.84) than men (OR 0.82, CI95 0.63-1.07) and also more striking for pulmonary embolism (OR 0.56, CI95 0.46-0.70) than for deep venous thrombosis of the leg (OR 0.74, CI95 0.63-0.88). Compared to abstainers, fibrinogen levels were decreased in individuals who consumed alcohol (maximum decrease: 0.30 g/l). Factor VII and von Willebrand levels were mildly decreased in these individuals but not consistently over the categories of alcohol consumption. In conclusion, alcohol consumption is associated with a reduced risk of venous thrombosis, which may be in part mediated by decreased fibrinogen levels.