Background: Although various predictors relating to in-stent restenosis (ISR) have been demonstrated, the relation between the parameters of intravascular ultrasound (IVUS) and inflammatory markers and ISR have not been reported. Methods: This study included 120 patients who underwent stent implantation for angiographically significant stenosis. Patients were divided into a soft plaque group (n = 50) and non-soft plaque group (n = 70) on the basis of pre-intervention plaque morphology. Results: The pre-procedural high-sensitivity C-reactive protein (hs-CRP) level was significantly higher in the soft plaque group. Soft plaque was detected in 73% of the ISR group and, in contrast, in only 27% of the non-ISR group. And ISR was observed in 44% of soft plaque group, in contrast, in only 11% of non-soft plaque group. The neointima area at the minimal lumen cross-sectional area at follow-up was significantly larger in the soft plaque group (3.7짹1.5 mm2 vs. 1.9짹1.5 mm2, p < 0.001). Only in soft plaque group, but not in non-soft plaque group, high hs-CRP level was associated with ISR significantly (63% vs. 15%, p < 0.001). By multivariate analysis, combination of the presence of soft plaque by pre-interventional IVUS examination and high pre-procedural hs-CRP level was the most significant independent predictor of ISR.