Background: Percutaneous coronary intervention (PCI) modulates platelet reactivity (PR). Objectives: To assess: (i) the impact of coronary interventions on periprocedural variations (¿) of PR; (ii) whether ¿PR correlates with periprocedural myocardial infarction (PMI); and (iii) the mechanisms of these variations in vitro. Methods and results: We enrolled 65 patients on aspirin (80–100 mg day-1) and clopidogrel (600 mg, 12 h before PCI): 15 with coronary angiography (CA group), 40 with PCI (PCI group), and 10 with rotational atherectomy plus PCI (RA group). PR was assessed by ADP, high-sensitivity ADP and thrombin receptor activator peptide 6 tests prior to, immediately after and 24 h after the procedure. E-selectin and ICAM-1 were assessed prior to and immediately after the procedure. In vitro, PR was measured during pulsatile blood flow at baseline, after balloon inflation and after stent implantation in six porcine carotid arteries and five plastic tubes. PR declined in the CA group, but significantly increased in the PCI and RA groups immediately postprocedure, and decreased to baseline at 24 h. ¿PR increased across the three groups (P <0.0001). In the PCI group, ¿PR was directly related to total inflation time (r = 0.435, P = 0.005) and total stent length (r = 0.586, P <0.001). The change in E-selectin significantly and inversely correlated with ¿PR (P <0.001). No correlation was found with sICAM-1. PR increased significantly more in patients with PMI than in patients without PMI (P = 0.013). In vitro, platelet activation was observed in the presence of carotid arteries but not in the presence of plastic tubes. Conclusions: Despite dual antiplatelet therapy, PCI affected platelet function proportionally to procedural complexity and the extent of vascular damage.