Background and Purpose— Smoking, increased fibrinogen levels, and platelet activation are related to the risk of ischemic stroke. The platelet fibrinogen receptor glycoprotein (Gp) IIb/IIIa Pl A1/A2 polymorphism affects the binding of platelets to fibrinogen and is suggested to interact with smoking. Methods— We explored the association of smoking and the Pl A1/A2 polymorphism with ischemic stroke and survival in the Stroke Aging Memory cohort, comprising 486 consecutive patients (55 to 85 years old) who were analyzed 3 months after an ischemic stroke and followed up for 15 months. Stroke subtype determined by magnetic resonance imaging and GpIIb/IIIa Pl A1/A2 genotype data were available for 272 patients. Results— In multivariate analysis, smoking was the only factor related to the risk of lacunar infarcts (odds ratio [OR]=1.87, 95% CI=1.05 to 3.31; P =0.033), and it was also a predictor of death (n=24, 8.8%) at 15 months (OR=5.13, 95% CI=1.61 to 16.36; P =0.006), along with age (OR=1.10, 95% CI=1.01 to 1.19; P =0.008). The GpIIb/IIIa Pl A1/A2 polymorphism alone showed no association with stroke subtype or survival. However, there was a smoking-by-genotype association with the risk of lacunar infarcts (OR=2.10, 95% CI=0.90 to 4.89; P =0.087) and with survival (OR=2.78, 95% CI=0.89 to 8.61; P =0.077). Among younger (55 to 69 years) stroke patients, smokers carrying the Pl A2 allele were at a higher (OR=5.81, 95% CI=1.26 to 26.80; P =0.024) risk of lacunar infarcts than noncarrier smokers (OR=3.12, 95% CI=1.06 to 9.24; P =0.039). The effect of Pl A2 and smoking combined on survival was also stronger (OR=8.86, 95% CI=1.68 to 46.55; P =0.010) than the effect of smoking alone (OR=5.06, 95% CI=1.20 to 21.35; P =0.027). Conclusions— Our results indicate that prothrombotic genetic factors may interact with smoking by modifying the stroke phenotype and affecting midterm survival.