Although on-site workstation-based CT fractional flow reserve (CT-FFR) is an emerging method for assessing vessel-specific ischemia in coronary artery disease, severe calcification is a significant factor affecting CT-FFR's diagnostic performance. The subtraction method significantly improves the diagnostic value with respect to anatomic stenosis for patients with severe calcification in coronary CT angiography (CCTA). We evaluated the diagnostic capability of CT-FFR using the subtraction method (subtraction CT-FFR) in patients with severe calcification. This study included 32 patients with 45 lesions with severe calcification (Agatston score >400) who underwent both CCTA and subtraction CCTA using 320-row area detector CT and also received invasive FFR within 90 days. The diagnostic capabilities of CT-FFR and subtraction CT-FFR were compared. The sensitivities, specificities, positive predictive values (PPVs), and negative predictive values (NPVs) of CT-FFR vs. subtraction CT-FFR for detecting hemodynamically significant stenosis, defined as FFR ≤ 0.8, were 84.6% vs. 92.3%, 59.4% vs. 75.0%, 45.8% vs. 60.0%, and 90.5% vs. 96.0%, respectively. The area under the curve for subtraction CT-FFR was significantly higher than for CT-FFR (0.84 vs. 0.70) (p = 0.04). The inter-observer and intra-observer variabilities of subtraction CT-FFR were 0.76 and 0.75, respectively. In patients with severe calcification, subtraction CT-FFR had an incremental diagnostic value over CT-FFR, increasing the specificity and PPV while maintaining the sensitivity and NPV with high reproducibility.