Conclusion: Patients at low risk for recurrent venous thromboembolism (VTE) can be identified by measurement of thrombin generation. Summary: Patients with VTE are often investigated for thrombophilic risk factors. The large number of potential thrombophilic risk factors makes this complex and expensive. The authors sought to determine whether the risk of recurrent VTE could be assessed by a global coagulation assay that measures thrombin generation. This was a prospective cohort study of 914 patients. All patients had a spontaneous VTE and were followed for an average of 47 months after discontinuation of oral anticoagulant therapy. The study period was from July 1992 to July 2005. A commercially available assay was used to measure thrombin generation. Excluded patients included those with secondary VTE, those with recurrent VTE, or those with a known thrombophilic risk factor such as antithrombin, protein C or protein S deficiencies, the presence of lupus anticoagulant, or cancer or pregnancy. The primary outcome measure was an objectively documented episode of recurrent VTE. VTE recurred in 100 patients (11%). There was lower thrombin generation in the patients without recurrent VTE compared with those with recurrent VTE (349.2 ± 108 nN vs 415 ± 110.5 nN, P < .001). In patients with thrombin generation values between 400 nN and 300 nN, the relative risk of recurrence compared to patients with thrombin generations >400 nN was 0.42 (95% confidence interval [CI], 0.26 to 0.67, P < .001). In patients with measured thrombin generations <300 nN relative risk was 0.37 (95% CI, 0.21 to 0.66, P = .001). For 4 years, the probability of VTE recurrence in patients with thrombin generation <400 nN was 6.5% (95% CI, 4.0% to 8.9%). In those patients with thrombin generation values >400, the probability of VTE recurrence was 20.0% (95% CI, 14.9% to 25.1%, P < .001). Patients with thrombin generation <400 nN had a 60% lower recurrence of VTE than those with greater values of thrombin generation (relative risk, 0.40; 95% CI, 0.27 to 0.60; P < .001. Comment: There are data to suggest that patients with idiopathic VTE benefit from longer periods of anticoagulation than those with VTE and a recognizable risk factor such as surgery or trauma. Given the implications of long-term anticoagulant therapy, it is desirable to identify which patients with idiopathic VTE are particularly prone to recurrence. If this study can be confirmed by others, measurement of thrombin generation may prove to be a relatively simple method of stratifying patients for their length of anticoagulation after a first time episode of idiopathic VTE.