This study prospectively evaluated the relationship between activated partial thromboplastin time (aPTT) and risk of venous thromboembolism (VTE) recurrence after oral anticoagulant (OA) withdrawal in patients with a previous unprovoked VTE event. Six hundred twenty-eight patients (331 males; median age: 67 years) were followed after OA interruption (mean follow-up = 22 months). Three to four weeks from OA discontinuation patients were given a complete thrombophilic work-out, including aPTT (automated aPTT). Recurrent symptomatic VTE events (objectively documented) occurred in 71/628 (11.3%, 6.8/100 person-years) patients. The VTE recurrence rate was 17.5% and 7.5% in patients with aPTT in the lower (ratio < or =0.90) and in the upper (ratio >1.05) quartiles. The recurrence risk was more than twofold higher in patients with ratio < or =0.90 versus those of the reference category [Relative risk (RR): 2.38 (95% confidence interval (CI): 1.18-4.78)]. As expected, the increase in recurrence risk disappeared after adjustment for factor VIII, IX and XI levels [RR: 1.74 (95%CI: 0.43-2.76)]. In contrast, the risk was persistently increased in patients with a ratio < or =0.90 [RR: 2.07 (95%CI: 1.02-4.18)] after adjustment for age, gender and d-dimer level. The aPTT predictive value was independent of the presence of inherited thrombophilic alterations. In conclusion, abnormally short aPTT values are associated with a significantly increased risk of VTE recurrence.