Background: Although several clinical trials have shown the superior efficacy and safety of second-generation everolimus-eluting stents (EES) in comparison with first-generationpaclitaxel-eluting stents (PES), the differences in the vascular healing process between EES and PES in a human coronary artery during an early stage are unknown. Methods: A prospectiveoptical coherence tomography (OCT) observation was performed for 25 EES in 21 patients and 27 PES in 21 patients at 6 months after implantation. Cross-sections within single-stent segments were analyzed at intervals of 1 mm. The neointimal (NI) thickness on each strut was measured. Uncovered struts (NI thickness = 0 μm), malapposed struts, NI area (%), uncovered strut ratio > 0.3 (UCSR; number of uncovered struts/number of total struts) per cross-section, and in-stent thrombus were evaluated. Results: A total of 5198 EES struts in 514 cross-sections and 4243 PES struts in 469 cross-sections were identified. NI thickness and its area were smaller for EES than PES (80.0 ± 84.8 μm vs. 117.9 ± 140.0 μm and 19.1 ± 8.9% vs. 23.7 ± 11.5%, respectively; P < 0.001). The frequencies of uncovered struts and malapposed struts were lower in EES compared to PES (2.3% vs. 5.2% and 2.1% vs. 5.7%, respectively; P < 0.001). Patients who had cross-sections of UCSR > 0.3 and thrombi were identified less frequently in EES than in PES group (5% vs. 57%; P < 0.001, and 19% vs. 48%; P = 0.05, respectively). Conclusions: Six-month OCT examination showed a favorable vessel healing response after the implantation of EES, demonstrating less in-stent late loss as well as fewer uncovered struts and better stent apposition to the vessel wall in comparison with PES.