Background Whether statin treatment can improve hemodynamic status of coronary atherosclerotic plaque remains unknown. It is of clinical interest to explore the hemodynamic change of coronary lesions after statin treatment. Methods and Results Consecutive patients with intermediate pre-test probability of coronary artery disease were prospectively enrolled and underwent baseline coronary computed tomography angiography (CCTA) as well as follow-up CCTA. The primary end point was to determine the lesion-specific change of △computed tomography-derived fractional flow reserve (△CT-FFR, defined as the change of CT-FFR value across each lesion) after rosuvastatin treatment. The secondary end point was to compare the change of other plaque characteristics according to serial CCTA findings. 152 patients (mean age: 67.1±9.7 years, 100 men, mean follow-up duration of 13.9±2.5 months) were finally included. In non-calcified plaque subgroup, △CT-FFR was significantly lower at follow-up compared with baseline (0.051±0.010 versus 0.035±0.012, =0.013). All other parameters were not found to be significantly different between baseline and follow-up CCTA measurements. In calcified plaque and mixed plaque subgroups, all parameters showed no significant differences between baseline and follow-up CCTA groups ( >0.05 for all). According to multivariate regression analysis, non-calcified plaque was >2 times more likely than calcified plaque to observe the decrease of △CT-FFR (adjusted hazard ratio: 2.05 1.03-4.09, =0.042). Conclusions In patients with mild to intermediate coronary stenosis, rosuvastatin treatment resulted in a reduction in lesion-specific △CT-FFR at mid-term follow-up. This hemodynamic improvement was mainly observed for non-calcified lesions.