Summary. Background: The risk of venous thrombosis associated with major illnesses is not well known, and neither is the risk associated with the combined effect of immobilization and thrombophilia. The aim of this study was to assess the effect on the development of venous thrombosis of several major illnesses in combination with immobilization, body mass index, and thrombophilia, to identify high-risk groups that may provide a basis for personalized prevention.Methods: This study included 4311 consecutive patients with a first episode of venous thrombosis, and 5768 controls from a case–control study (MEGA study). We calculated odds ratios (ORs) for venous thrombosis for patients with a self-reported history of major illnesses.Results: Venous thrombosis risk was increased for all investigated major illnesses: liver disease, OR 1.7 (95% confidence interval [CI] 1.0–2.9); kidney disease, OR 3.7 (95% CI 2.3–5.9); rheumatoid arthritis, OR 1.5 (95% CI 1.2–1.9); multiple sclerosis, OR 2.4 (95% CI 1.3–4.3); heart failure, OR 1.7 (95% CI 1.2–2.3); hemorrhagic stroke, OR 4.9 (95% CI 2.4–9.9); arterial thrombosis, OR 1.5 (95% CI 1.2–1.8); and the presence of any of the above major illnesses, OR 1.7 (95% CI 1.5–1.9). Combinations of major illnesses with immobilization and increased factor VIII (OR 79.9; 95% CI 33.2–192.2), increased FIX (OR 35.3; 95% CI 14.2–87.8), increased von Willebrand factor (OR 88.0; 95% CI 33.9–228.3), FV Leiden (OR 84.2; 95% CI 19.5–363.6), and blood group non-O (OR 53.1; 95% CI 30.9–91.4) were associated with increased venous thrombosis risks.Conclusions: All of the major illnesses reported here were associated with an increased risk of venous thrombosis. These risks were most pronounced at the time of immobilization or in the presence of thrombophilia.