Although various predictors relating to in-stent restenosis (ISR) have been demonstrated, the relation between the parameters of intravascular ultrasound and inflammatory markers and ISR has not been reported. This study included 120 patients who underwent stent implantation for angiographically significant stenosis. Patients were divided into a soft plaque group (n = 50) and a nonsoft plaque group (n = 70). All patients underwent angiographic and intravascular ultrasound follow-up at 6 months. The baseline high-sensitivity C-reactive protein (hs-CRP) level was significantly higher in the soft plaque group. The follow-up minimal lumen diameter was significantly smaller in the soft plaque group. Soft plaque was detected in 73% of the ISR group but only 27% of the non-ISR group. Also, ISR was observed in 44% of the soft plaque group in contrast to only 11% of the nonsoft plaque group. The neointimal area at the minimal lumen cross-sectional area at follow-up was significantly larger in the soft plaque group (3.7 +/- 1.5 vs 1.9 +/- 1.5 mm2, p < 0.001). In conclusion, in patients with soft plaque, an elevated hs-CRP level was significantly associated with ISR (63% vs 15%, p < 0.001). By multivariate analysis, the combination of soft plaque and elevated hs-CRP was the most significant independent predictor of ISR.