Sirolimus-eluting stents (SES) have reduced the incidence of restenosis and target lesion revascularization compared to bare metal stents (BMS). However, inhibition of endothelialization and neointimal formation after SES implantation may produce vulnerable plaques. The present study compared the neointimal morphology of in-stent restenosis (ISR) between SES and BMS using virtual histology-intravascular ultrasound (VH-IVUS). Thirty ISR lesions (SES n = 15, BMS n = 15) demonstrated by coronary angiography in 30 patients with stable angina pectoris were analyzed with VH-IVUS between 6 months to 3 years after stent implantation. Tissue maps were reconstructed from radiofrequency data using VH-IVUS software. ISR lesions after SES implantation consisted of a significantly increased necrotic core (NC) compared to BMS (12.9 vs. 5.6% of neointimal volume, p < 0.01). However, the NC in ISR lesions after SES implantation was covered with a thick fibrous cap. An increase in the size of NC covered with a thick fibrous cap is a characteristic morphological feature of ISR after SES implantation. Further studies are needed to clarify whether such a morphological change is related to the attenuation of stent thrombosis after SES implantation.