A hypercoagulable state has been reported in some patients treated for venous thromboembolism (VTE) after oral anticoagulant treatment (OAT) discontinuation. It is unclear whether this is a risk factor for thrombosis recurrence. We investigated 139 patients with VTE and followed them up for a median of 20.5 months (6-90 months) to evaluate whether fragment 1 + 2 (F1 + 2) plasma levels are prognostic for VTE recurrence and to confirm clotting activation after OAT withdrawal. Fourteen patients had recurrences during the follow-up. F1 + 2 was measured the day before OAT withdrawal (T0) and 4 weeks later (T1) and its levels were similar in patients with spontaneous VTE versus those with transient risk factors for VTE. F1 + 2 levels increased from T0 to T1 (P < 0.0005). At T1, F1 + 2 values were significantly higher in patients with recurrence than in those without (P < 0.005). The negative predictive value of normal levels of F1 + 2 at T1 was 95%. In carriers of thrombophilic conditions no correlation was found between F1 + 2 levels and VTE recurrence. The results of this study confirm clotting activation after OAT discontinuation and suggest that higher F1 + 2 plasma levels are an independent risk factor for VTE recurrence.