It is widely accepted that influenza vaccination reduces the risk of cardiovascular events in patients with coronary artery diseases. However, no information is available concerning the role of influenza vaccination in venous thromboembolism (VTE). Methods: A case-control study was conducted in 727 cases and 727 age and sex-matched controls from 11 centers in France (the FARIVE study). Cases were patients with a first documented episode of VTE and without any personal history of cancer within the last 5 years; controls were recruited in the same hospital and had no personal history of venous or arterial thrombosis. Results: Overall, 202 (28.2%) of cases and 233 (32.1%) of controls had influenza vaccination during the previous 12 months at the time of recruitment. Information was not available for only 12 subjects out of 1454. The crude odds ratio (OR) for VTE associated with influenza vaccination was 0.76 (95% CI 0.58–0.99). After adjustment for potential confounding variables (age, sex, inclusion date, BMI, educational levels and varicose veins), the OR for VTE associated with vaccination was 0.74 (95% CI 0.57–0.97). The protective effect of vaccination toward VTE was higher in the population below 52 years (median of age), with an OR of 0.52 (95% CI 0.32–0.85). In women below the age of 51, the crude OR for VTE associated with influenza vaccination was 0.50 (95% CI 0.24–1.05) and was significant after adjustment for confounding variables including oral contraceptives, with an OR of 0.41 (95% CI 0.19–0.92). The protective effect of vaccination was similar for different types of VTE (DVT or PE). There was no statistical differences in the protective effects when we compared provoked with unprovoked VTE events. Conclusion: This is the first study that demonstrates a protective effect of influenza vaccination in VTE. In vitro influenza induces activation of coagulation and inflammation but we cannot rule out that the protective effect of influenza vaccination was due to other unknown mechanisms, as the protective effect was similar within the different seasons of the year. Influenza vaccination may reduce the risk of VTE by 26%. This relationship between influenza vaccination and VTE and its underlying mechanism still need to be analyzed and confirmed in further studies.