The role of the fibrinolytic system in the development of deep vein thrombosis (DVT) is unclear. We determined the plasma fibrinolytic potential of patients enrolled in the Leiden Thrombophilia Study (LETS), a population-based case-control study on risk factors for DVT. Plasma fibrinolytic potential was determined in 421 patients and 469 control subjects by means of a tissue factor-induced and tissue-type plasminogen activator (tPA)-induced clot lysis assay. Using clot lysis times above the 70th, 80th, 90th, 95th, and 99th percentiles of the values found in control subjects as cut-off levels, we found a dose-dependent increase in risk for DVT in patients with hypofibrinolysis (odds ratios of 1.4, 1.6, 1.9, 2.1, and 2.2, respectively). This indicates a 2-fold increased risk of DVT in subjects with clot lysis times above the 90th percentile. The risk increase was not affected by age or sex (adjusted odds ratio for 90th percentile, 2.0), and after correction for all possible confounders (age, sex, and levels of procoagulant proteins shown to associate with clot lysis times in the control population), the risk estimate was marginally reduced (odds ratio, 1.6 for 90th percentile). Taken together, these results indicate that plasma hypofibrinolysis constitutes a risk factor for venous thrombosis, with a doubling of the risk at clot lysis times that are present in 10% of the population.