BACKGROUND: Factors that predict the risk of venous thromboembolism in the first-degree relatives of patients with unprovoked venous thromboembolism are uncertain but important for counseling. We aimed to identify risk factors for, and quantify the risk of, venous thromboembolism in first-degree relatives of patients (index case patients) with a first episode of unprovoked venous thromboembolism. METHODS: In a cross-sectional study, using a standardized method and without knowledge of whether patients or their relatives had thrombophilia, we assessed the prevalence of previous venous thromboembolism in 1,916 first-degree relatives of 378 unselected patients with a first episode of unprovoked venous thromboembolism. Patient characteristics, and the presence of factor V Leiden or the G20210A prothrombin gene mutation in patients, were assessed as predictors of venous thromboembolism in patient's relatives. RESULTS: There were 102 previous episodes of venous thromboembolism in the first-degree relatives (prevalence, 5.3%). Thrombosis at a young age in patients was the strongest predictor of venous thromboembolism in relatives, with an adjusted odds ratio (OR) for younger patients (ie, patients 71 years of age; highest quartile) of 3.27 (95% CI, 1.68 to 6.38). The presence of factor V Leiden or the G20210A prothrombin gene in patients was a weak independent predictor of venous thromboembolism in relatives (adjusted OR, 1.48; 95% CI, 0.94 to 2.33). CONCLUSION: Unprovoked venous thromboembolism at a young age is associated with a substantially increased risk of venous thromboembolism in patients' families.