Objectives: Diagnostic accuracy of conventional coronary CT angiography (CCTA conv ) may be compromised by blooming artifacts from calcifications or stents. Blooming artifacts may be reduced by subtraction coronary CT angiography (CCTA sub ) in which non-contrast and contrast CT data sets are subtracted digitally. We tested whether CCTA sub in patients with severe coronary calcification or stents reduces the number of false-positive stenosis evaluations compared with CCTA conv ., Methods: In this study, 180 symptomatic patients scheduled for invasive coronary angiography (ICA) were prospectively enrolled and CT scanned (2013-2016) at three international centers. CCTA conv , and CCTA sub data sets were reconstructed. Target segments were defined as motion-free coronary segments with a suspected stenosis (> 50% of lumen) potentially due to blooming of either calcium or stents. Target segments were evaluated with respect to misregistration artifacts from the CCTA sub reconstruction process, in which case evaluation was omitted. CCTA sub and CCTA conv were compared with ICA. Primary outcome measure was the frequency of false positives by CCTA conv versus CCTA sub to identify > 50% coronary stenosis by ICA on a per-segment level., Results: After exclusion of 76 patients, 104 (14% females) with mean age 67 years and median Agatston score 852 were included. There were 136 target segments with misregistration and 121 target segments without. Accuracy calculations in target segments without misregistration showed a reduction of the false positives from 72% [95% confidence interval (CI): 63-80%] in CCTA conv to 33% (CI:25-42%) in CCTA sub , at the expense of 7% (CI:3-14%) false negatives in CCTA sub ., Conclusions: In severely calcified coronary arteries or stents, CCTA sub reduces the false-positive rate in well-aligned, calcified or stent segments suspected of significant stenosis on CCTA conv . Nevertheless, misregistration artifacts are frequent in CCTA sub ., Key Points: • A high calcium-score reduces the diagnostic accuracy in patients scanned with cardiac CT. • These patients would normally need an invasive angiogram for diagnosis. • In this prospective, multicenter study, subtraction CT, when evaluable, reduces false-positive stenosis evaluations. • Subtraction coronary CT angiography may, when evaluable, reduce excessive downstream testing.