The aim of this study was to assess in-stent restenosis (ISR) of coronary artery for patients with CoCr stent using subtraction coronary computed tomography angiography (CCTA) with one-breath-hold scan on 320-row area detector CT, invasive coronary angiography (ICA) as clinical standard. Patients who were referred for CCTA from January 2020 to May 2021 were retrospectively analyzed. Pre-contrast and CCTA was performed with dedicated one-breath-hold subtraction scan protocol and post processing to get subtracted-CCTA image without stent. Subjective image qualities and diagnosable rate were analyzed for CCTA and subtracted-CCTA respectively. The ISR degree of each stent was evaluated both on CCTA and subtracted-CCTA images. The receiver-operating characteristic curve with sensitivity, specificity, accuracy of CCTA, and subtracted-CCTA in the diagnosis of ISR were calculated with ICA as reference. Forty patients with 85 CoCr coronary stents of 3 to 3.5 mm diameter with ICA confirmation within 1 month were finally included. Subtracted-CCTA showed more diagnosable segments of stent (91.76% [78/85]) than those of CCTA (50.59% [43/85]) ( P < .001). The subjective image quality score of CCTA was 2.23 ± 1.32 while 3.41 ± 0.90 on subtracted-CCTA ( P < .001). Both subtracted-CCTA and CCTA showed high consistency with ICA (Kappa = 0.795 and 0.918 respectively). The area under the curve was 0.607 for CCTA and 0.757 for subtracted-CCTA ( P < .001) for stent based diagnose, respectively. The sensitivity, specificity, accuracy of CCTA, and subtracted-CCTA were 90.0%, 97.0%, 95.3%, and 87.5%, 100.0%, 97.43%, respectively. Subtracted-CCTA showed improved diagnose performance for ISR, which potentially reduce further follow-up ICA procedures for patients with CoCr stents.