Intra-stent thrombus (IS-Th) formed immediately after percutaneous coronary intervention (PCI) is associated with subsequent adverse coronary events. However, the impact of on-treatment platelet reactivity on IS-Th is unknown. PRASFIT-Elective is a multicenter study of PCI patients receiving prasugrel (20/3.75 mg, loading/maintenance dose) or clopidogrel (300/75 mg), with aspirin (100 mg). Among the 742 study patients, 111 were pre-specified for the OCT sub-study. Of these, 82 underwent OCT immediately after PCI to assess IS-Th and at an 8-month follow-up to evaluate the fate of the IS-Th. Lesions were considered resolved when IS-Th were detected after PCI but not on the follow-up or persistent when IS-Th were observed on both scans. The P2Y12 Reactive Unit (PRU) value was determined at the initial PCI and 4 and 48 weeks post-PCI. In 76 patients (86 lesions), we detected 230 IS-Th initially, and 196 IS-Th (85.2%) were resolved at the 8-month OCT. At PCI, but not 4 or 48 weeks after, the resolved IS-Th group had a lower PRU than the persistent IS-Th group (199 ± 101 vs. 266 ± 102, p = 0.008). Multivariate logistic regression analyses revealed that lower PRU at PCI and less calcified lesions were independent predictive factors for the resolution of IS-Th. Local lesion-related factors and lower on-treatment platelet reactivity at the time of PCI may contribute to the resolution of IS-Th after EES implantation, potentially improving clinical outcome.