This prospective study was designed to investigate whether patients with short activated partial thromboplastin times (aPTTs) have increased thrombin generation and are at increased risk for thromboembolism. During a 4-month period, routine coagulation specimens were screened for the presence of a short or normal aPTT, and, accordingly, 250 specimens were collected. Prothrombin fragment F1 + 2 (F1 + 2) was measured to evaluate thrombin activation, and a second aPTT was performed with a different reagent. Diagnoses were obtained from medical records after conclusion of sample collection. Five to 9 months later, patients were questioned on thromboembolic events during the previous 18 months by questionnaire and telephone interview. F1 + 2 and the incidence of venous thromboses were elevated significantly in the short aPTT group. Unexpectedly, patients with acute bleeding had short aPTTs, but 36% of these also had thromboembolic events during the 18 months proximal to blood collection. These findings were confirmed with the second aPTT reagent. Patients with short aPTTs have increased thrombin generation and are at increased risk for thromboembolism, mainly venous thromboses, despite the fact that a short aPTT can occur in the acute setting of bleeding.