Echolucent carotid plaques are associated with higher risk for future ischemic cerebrovascular events (CVE) than echogenic plaques independent of the degree of stenosis. Elevated markers of thrombin generation are associated with atherosclerotic plaques and are increased in the acute and chronic phases of CVE. The present study was conducted to investigate the influence of plaque morphology on thrombin generation in persons with carotid stenosis. One hundred twenty-eight persons with carotid stenosis (>or=35% lumen diameter reduction) and 136 matched controls without stenosis were recruited from the health survey of the Tromsø Study. Blood samples were collected and plaque morphology determined by ultrasonography. Thrombin generation was assessed by thrombin-antithrombin complexes (TAT) and by prothrombin fragment 1+2 (F1+2). Persons with echogenic plaques (n = 63) had significantly higher levels of TAT (5.24 microg/l, 4.33-6.14) (mean, 95%CI) than persons with echolucent plaques (n = 65) (3.44 microg/l, 2.91-3.96, p < 0.001) and controls (n = 136) (3.33 microg/l, 3.06-3.60, p < 0.001). They also had significantly higher levels of F1+2 (2.14 nM, 1.83-2.45) than persons with echolucent plaques (1.54 nM, 1.38-1.71, p < 0.001) and controls (1.49 nM, 1.40-1.58, p < 0.001). TAT and F1+2 increased linearly with plaque echogenicity (p = 0.002 and p = 0.001, respectively) independent of the degree of stenosis. Increased thrombin generation was associated with a significant increase in plasma factor V levels among persons with echogenic plaques compared to echolucent plaques (p = 0.049) and controls (p = 0.025). The present findings indicate that increasing plaque echogenicity, rather than plaque echolucency and the degree of stenosis, is associated with thrombin generation in persons with carotid stenosis.