The mechanism of statin for atheroma stabilization remains unclear. We aimed to assess the relationship between on-treatment changes in serum inflammatory biomarker levels and plaque composition in differed nonculprit coronary lesions. The changes in serum biochemical values, and intravascular ultrasound data were evaluated in 218 patients with virtual histology (VH)-intravascular ultrasound-defined fibroatheroma-containing segments after 12-month rosuvastatin treatment. When stratifying patients into quartiles according to the change in high-sensitivity C-reactive protein (hsCRP), there was a significant positive linear relationship for the changes in %necrotic core (coefficient, 1.31; standard error, 0.54) and %dense calcium volumes (coefficient, 0.80; standard error, 0.27), but a negative linear relationship for the changes in %fibrous (coefficient, -0.94; standard error, 0.45) and %fibrofatty volumes (coefficient, -1.17; standard error, 0.56; all P<0.05). The decrease in hsCRP (-1.2±3.9 versus 0.5±3.4 mg/L; P=0.02) was greater in those without VH-defined thin-cap fibroatheroma (TCFA, defined as >30° of necrotic core abutting the lumen in 3 consecutive slices) than those with VH-TCFA at follow-up. Diabetes mellitus, a larger normalized total atheroma volume, and the presence of VH-TCFA at baseline predicted the presence of VH-TCFA at follow-up (odds ratio, 4.01, 1.18, and 9.21, respectively; all P<0.05), whereas the change in hsCRP showed a trend (odds ratio, 1.19; P=0.07). The change in low-density lipoprotein-cholesterol had no relationship with the changes in hsCRP or plaque compositions. With 12-month rosuvastatin therapy, a greater hsCRP reduction (not low-density lipoprotein-cholesterol) was associated with a greater decrease in %necrotic core volume and the absence of VH-TCFA, indicating a link between the anti-inflammatory action of statin and plaque stabilization by reducing NC and reinforcing fibrous cap. URL: https://www.clinicaltrials.gov. Unique identifier: NCT00997880.