Background: Paclitaxel-Coating balloon (PCB) has shown efficacy for treatment of coronary artery disease. Optical coherence tomography (OCT) is a promising endovascular imaging devise and has been reported to have a high correlation with histomorphometric measurement. However, the association of in-stent stenosis (ISR) by OCT and histopathology response is still not fully addressed. The current study was designed to compare the OCT and histopathological findings following PCB treatment in a porcine ISR model. Materials and Methods: Thirty-two coronary arteries (LAD: n=12, LCX: n=11, RCA: n=9) of 24 Yorkshire pigs were assigned to two (2) groups randomly. PCB (SeQuent, length 20mm, n=16) or non-coating balloon (NCB, length 20mm n=16) were inflated for 60 seconds with B:A 1.2:1 followed by BMS (length 12mm) implantation (S/A 1.5:1) within the target region. At 28 days, animals underwent OCT and histopathology evaluation. Results: There were no significant differences between groups among parameters measured by OCT. The thickness of neointimal hyperplasia on stent strut and the percent of ISR were 585 ± 277 μ m, 46.8 ± 19.0 % for PCB, and 661 ± 237 μ m, 52.4 ± 15.3 % for NCB (p=NS, respectively). However, inflammation (PEB: 3.40 ± 0.84, NCB: 2.27 ± 1.18, p=0.003) and fibrin deposition scores (PCB: 2.31 ± 0.93, NCB: 0.81 ± 0.86, p<0.001) were significantly higher in PCB compared to NCB. The OCT ISR% was positively correlated with inflammation score (PCB: r=0.62, and NCB: r=0.85; p<0.05 respectively). Interestingly, fibrin deposition score only in PCB was negatively correlated with the OCT ISR% (r=-0.68, p=0.005). OCT also showed an uncovered (33.3%) and insufficient non-uniformed neointima (13.3%) in PCB group (p=0.008 vs NCB). Conclusions: OCT can be used as a valuable imaging tool to evaluate vessel wall histopathological changes in vivo. The higher inflammation and fibrin deposition scores in PCB may indicate a delayed healing response in the current experimental setting.