Objective To explore effects of long-term smoking on secondary prevention for oral aspirin in high-risk stroke patients. Methods A total of 115 high-risk stroke patients who orally took aspirin for secondary prevention in our hospital from August 2012 to August 2014 were selected as the study subjects. According to smoking or not, they were divided into non smoking history group (34 cases) and smoking history group (81 cases). Among them, 36 cases whose smoking time was ≥ 20 years were included in the long-term smoking history group, and 45 cases whose smoking time was 1 to 19 years were included in the short-term smoking history group. The patients were followed up for 12 months. The platelet granule membrane protein (GMP-140), D-dimer (D-D), fibrinogen (FIB), tissue plasminogen activator (t-PA), platelet membrane glycoprotein CD61 and CD62p were determined. The incidence rates of 1-year aspirin resistance and clinical outcome events in the three groups were recorded. Results Before and after treatment, GMP-140, D-D, FIB, CD61 and CD62p in long-term smoking history group were higher than those in short-term smoking history group and non smoking history group while T-PA was lower, and there were significant differences between short-term smoking history group and non smoking history group (P<0.05). The incidence rates of aspirin resistance and clinical outcome events in long-term smoking history group (33.33%, 30.56%) were higher than those in non smoking history group (8.82%, 8.82%)(P<0.05), but there was no significant difference among other groups (P>0.05). Conclusion Long-term smoking history will cause prethrombotic state in stroke patients and increase the incidence rates of aspirin resistance and clinical outcome events.