Negative CCTA can effectively exclude significant CAD, eliminating the need for further noninvasive or invasive testing. However, in the presence of severe CAD, the accuracy declines, thus necessitating additional testing. The aim of our study was to evaluate the diagnostic performance of noninvasive cFFR derived from CCTA, compared to ICA in detecting hemodynamically significant stenoses in participants with high CAC scores (>400). This study included 37 participants suspected of having CAD who underwent CCTA and ICA. CAC was calculated and cFFR analyses were performed using an on-site machine learning-based algorithm. Diagnostic accuracy parameters of CCTA and cFFR were calculated on a per-vessel level. The median total CAC score was 870, with an IQR of 642-1370. Regarding CCTA, sensitivity and specificity for RCA were 60% and 67% with an AUC of 0.639; a LAD of 87% and 50% with an AUC of 0.688; an LCX of 33% and 90% with an AUC of 0.617, respectively. Regarding cFFR, sensitivity and specificity for RCA were 60% and 61% with an AUC of 0.606; a LAD of 75% and 54% with an AUC of 0.647; an LCX of 50% and 77% with an AUC of 0.647. No significant differences between AUCs of coronary CTA and cFFR for each vessel were found. Our results showed poor diagnostic accuracy of CCTA and cFFR in determining significant ischemia-related lesions in participants with high CAC scores when compared to ICA. Based on our results and study limitations we cannot exclude cFFR as a method for determining significant stenoses in people with high CAC. A key issue is accurate and detailed lumen segmentation based on good-quality CCTA images.