Risk of venous thrombosis is increased after long-distance travel. Identifying high-risk groups may provide a basis for targeted prevention. We assessed the effect of increased levels of coagulation factors and combinations of risk factors in travelers in a large case-control study. We calculated odds ratios (ORs) for 334 travelers (200 cases and 134 controls) with coagulation factors II (prothrombin), VII, VIII, and IX; fibrinogen, and von Willebrand factor (VWF) above the 80th percentile; for increasing numbers of risk factors; and for specific combinations. The risk was increased in travelers with high FII (OR, 2.2: 95% CI, 1.3-3.7) and FVIII (OR, 6.2, (95% CI, 3.6-10.5) compared with travelers with normal levels. High FIX and fibrinogen levels increased the risk in air travelers (FIX: OR, 3.2; 95% CI, 0.9-11.0; fibrinogen: OR, 2.0; 95% CI, 0.7-5.5) but not in other travelers. The ORs increased with the number of risk factors, and the risk was increased most in women with the combination of oral contraceptives and high FVIII (OR, 51.7; 95% CI, 5.4-498). We conclude that increased levels of FII and FVIII increase the risk of venous thrombosis in travelers. Furthermore, the risk is greatly increased if other risk factors are present as well.