Background: The frequency and role of risk factors for venous thromboembolism related to air travel is uncertain. We aimed to establish the frequency of this disorder in a group of long distance air travellers and to investigate the role of potential risk factors. Methods: We designed a prospective study into which we recruited individuals aged between 18 and 70 years, travelling for 4 h or more by aircraft. D-dimer measurement was done before and after travel. Participants with a negative D-dimer (<500 ng/L) before travel were included in the study. Those who became D-dimer positive or developed high clinical probability symptoms during the 3 months after travel were investigated with bilateral compression ultrasonography and CT pulmonary angiography. Suspected clinical and thrombophilic risk factors, and use of prophylactic measures, were assessed. Findings: 1000 individuals were recruited, with 878 meeting inclusion criteria and completing the study. All participants travelled at least 10 h, with a mean total duration of air travel of 39 h (SD 12.5). 112 patients underwent radiological assessment on return. Frequency of venous thromboembolism associated with travel was 1.0% (9/878, 95% CI 0.5-1.9), which included four cases of pulmonary embolism and five of deep venous thrombosis. Six patients with venous thromboembolism had pre-existing clinical risk factors, two had a recognised thrombophilic risk factor, two travelled exclusively in business class, five used aspirin, and four wore compression stockings. Interpretation: Our results suggest an association between multiple long distance air flights and venous thromboembolism, even in individuals at low to moderate risk. The role of traditional risk factors and prophylactic measures in air travel-related venous thromboembolism needs further investigation.