A number of polymorphisms of the platelet glycoprotein (GP) Ib-V-IX and IIb/IIIa complexes have been described, and the PlA polymorphism of GP IIIa has been associated with coronary thrombosis. We determined the levels of beta-thromboglobulin (beta-TG) and platelet factor 4 (PF4) and the genotype distributions of PlA and a variable number tandem repeat (VNTR) polymorphism of GP 1b in subjects with acute stroke (n=609) and healthy control subjects (n=435). Levels of beta-TG were higher in patients both initially (47.4 [44.7 to 50.2] ng/mL, P<0.0001) and after 3 months (42.9 [40.3 to 45.7] ng/mL, P=0.03) compared with control subjects (39.4 [37.7 to 41.2] ng/mL). Initial levels of beta-TG were significantly higher in those who subsequently died (58.7 [52.3 to 65.8] ng/mL) compared with those still alive (42.7 [40.1 to 45.5] ng/mL, P<0.0001). In a logistic regression model, beta-TG remained an independent predictor of poststroke mortality, with an odds ratio for an increase in 10 ng/mL of 1.12 (1.03 to 1.21, P=0.006). In subjects who had never smoked, there was a significant difference in the genotype distributions of patients with atherothrombotic stroke (A1/A1=147, A1/A2=70, and A2/A2=2) compared with controls (A1/A1=165, A1/A2=47, and A2/A2=5, P=0.03). The PlA distribution of subjects with atherothrombotic stroke before the age of 50 years (A1/A1=19 and A1/A2+A2/A2=18) was also significantly different from age- and sex-matched controls (A1/A1=54 and A1/A2+A2/A2=20, P=0.02). We found no association of VNTR with stroke or poststroke mortality. These data indicate that there is a persistent state of enhanced platelet activation in subjects with acute stroke, which is associated with poststroke mortality. The increased frequency of the PlA2 allele in young subjects with atherothrombotic stroke lends further support for a role of the PlA polymorphism in acute thrombosis.