Acute coronary syndromes (ACSs) represent a high-risk condition, as enhanced platelet reactivity importantly influences myocardial perfusion and procedural results after percutaneous coronary intervention (PCI). In fact, higher rate of periprocedural myocardial infarction (PMI) and reduced event-free survival have been reported in these patients. The single nucleotide polymorphism Leu33Pro of platelet glycoprotein IIIa has been related to an increased platelet reactivity, a lower response to antiplatelet agents and higher risk of stent restenosis. Therefore, our aim was to evaluate the impact of this polymorphism on PMI in patients undergoing PCI for non-ST-segment elevation MI (NSTEMI). Our population is represented by 478 consecutive patients undergoing coronary angioplasty for NSTEMI. Cardiac biomarkers were monitored at intervals from 8 to 48 h after the procedure. Genetic analysis was performed to assess the presence of Leu33Pro polymorphism. A total of 156 patients (32.6%) were polymorphic. Clinical features did not differ according to genetic status, neither pharmacological treatment pre and during angioplasty. PlA carriers had lower rate of calcifications (P = 0.01) and higher coronary tortuosity (P = 0.03) at angiography and underwent more frequently to thrombectomy (P = 0.05). PCI-related complications did not differ according to genotype. Leu33Pro polymorphism was not associated with increased risk of periprocedural myonecrosis and PMI even after correction for baseline differences, [odds ratio (OR) (95% confidence interval (CI) = 0.70 (0.44-1.13), P = 0.15 for PMI and OR (95% CI) = 0.77 (0.53-1.11), P = 0.17 for myonecrosis, respectively]. Results were confirmed in high-risk subgroups of patients. In conclusion, among patients undergoing PCI for ACS, the polymorphism Leu33Pro of platelet glycoprotein IIIa is not associated with increased risk of PMI.