Platelet volume is a marker of platelet function and activation. An elevated mean platelet volume (MPV) is associated with acute coronary syndromes (ACS). Recurrent cardiovascular events were found to be higher in patients with aspirin resistance. In this study, we investigated the effect of MPV on prognosis of patients with and without aspirin resistance by PFA-100 in settings of non-ST-segment elevated ACS. Two hundred and twenty patients with ACS were followed for an average of 14.86 +/- 5.93 months for the occurrence of death, myocardial infarction (MI) and revascularization. Aspirin effect on platelet function was assessed by PFA-100. According to MPV value and aspirin resistance status, patients were divided into four groups. Group 4 (with an elevated MPV and aspirin resistance) was significantly associated with worse prognosis for composite endpoint (death, MI and revascularization), death and MI (for all, log-rank P < 0.0001). Multivariate analysis showed that presence of an elevated MPV and aspirin resistance was an independent predictor of composite endpoint [hazard ratio 8.21, 95% confidence interval (CI) 3.48-19.35, P < 0.0001], death (hazard ratio 5.48, 95% CI 1.62-18.53, P = 0.006) and MI (hazard ratio 4.44, 95% CI 1.57-12.58, P = 0.005). Presence of an elevated MPV and aspirin resistance was significantly associated with death, MI and the composite endpoint, due to the lack of beneficial effect of aspirin on activated platelets. Patients with ACS, especially in the presence of an elevated MPV may benefit from the evaluation of aspirin resistance for risk stratification.