Aspirin resistance and its predictors were studied in community hospital patients who required antiplatelet therapy for thrombotic event prophylaxis. Demographic and antiplatelet medication data were collected and medication response followed. Aspirin resistance was assayed with the VerifyNow System with > or = 550 aspirin reaction units (ARUs) used as a dichotomous indicator of aspirin resistance. Patients (n = 123) were 21 to 95 years old; 49.6% were women, 77.2% were black, 95.1% were hypertensive, 85.4% had coronary disease, and 30.1% were smokers. ARU score for 325 versus 81 mg/day was 435.2 +/- 93.7 versus 401.9 +/- 83.9 ARU (p = 0.04), with a 12.1% (8 of 66 patients) nonresponse rate to 81 mg/day. Of the 8 patients who were unresponsive to 81 mg/day of aspirin, 7 responded to 325 mg/day. The 5.3% (3 of 57 patients) who were resistant to 325 mg/day received clopidogrel; 2 became responders. Multivariate analysis demonstrated significant associations of aspirin resistance with smoking (risk ratio 11.47, 95% confidence interval 6.69 to 18.63, p < 0.0001), including a significant interaction between smoking and aspirin resistance. In conclusion, this study estimates aspirin resistance prevalence and shows a strong association of smoking with platelet hyperactivity in a diverse community hospital population. Nonresponders to 81 mg/day frequently responded to 325 mg/day or to the addition of clopidogrel.