After an episode of unstable angina or myocardial infarction, a high proportion of patients show biochemical signs of coagulation activation, expressed as persistently elevated thrombin generation, in their blood. It is not known whether this has any influence on long-term outcome. In this prospective multicenter cohort study, we assessed the relation of persistently elevated thrombin generation to outcome in 319 consecutive patients with acute coronary syndromes enrolled in the Global Use of Strategies To Open occluded coronary arteries (GUSTO) IIb trial. Plasma prothrombin fragment 1 + 2 levels, an index of "in vivo" thrombin generation, was measured during the acute phase and after 1, 6, and 12 months, and its relation to outcome was assessed during a median 29-month follow-up period. The primary end point of cardiac death or myocardial (re)infarction occurred in 61 patients (19%). There was a U-shaped relationship between plasma prothrombin fragment 1 + 2 levels and the risk of developing the primary end point; intermediate levels (1.5-1.9 nM) were associated with the lowest risk, whereas both higher (> 1.9 nM) and lower (< 1.5 nM) values were associated with an increased risk (relative risk [RR] 1.56 and 95% confidence interval [CI], 1.25-2.28; RR, 1.35 and 95% CI, 1.11-1.86, respectively). After an episode of acute coronary syndrome, both high and low levels of thrombin generation are predictors of an increased risk of an unfavorable outcome.