Abstract Background/Introduction The use of coronary computed tomography angiography (CCTA) in managing high-risk acute coronary syndrome (ACS) patients is increasingly common. Yet, its role remains unvalidated in this context, posing challenges to traditional clinical decision-making algorithms. Physicians, accustomed to a hierarchical and structured approach involving symptom assessment, electrocardiograms, and biomarkers for deciding on the necessity of invasive coronary angiography (ICA), now face dilemmas when CCTA results challenge established diagnostic pathways and contradict clinical decisions based on usual criteria. Meanwhile, the potential of artificial intelligence (AI) which processes information in a way fundamentally different from human clinical reasoning, has been shown to aid decision-making in cardiovascular medicine. Yet, it has not been tested in this acute setting. Purpose This study aimed to evaluate the efficacy of the Chat Generative Pre-trained Transformer (ChatGPT) in guiding the need for ICA in high-risk ACS patients based on both standard clinical data and CCTA findings. Methods This investigation is a sub-study of a larger research project where high-risk ACS patients (all having a theoretical guideline-based indication for ICA) underwent CCTA prior to ICA. ChatGPT analyzed clinical vignettes containing patient data, electrocardiograms, troponin levels, and CCTA results to determine the necessity of ICA. The AI's recommendations were then compared to actual ICA findings to assess its decision-making accuracy. Results Among 86 patients with a clear indication for ICA, ChatGPT recommended against it for 19 patients, 16 of whom indeed had no significant findings at ICA (Figure). For 67 patients, ChatGPT advised proceeding with ICA, and a significant lesion was confirmed in 58 of them. Consequently, ChatGPT's overall accuracy stood at 86%, with a sensitivity of 95% and a specificity of 64%. The model's negative predictive value was 84%, and its positive predictive value was 87%. Conclusion These preliminary data suggest that ChatGPT can effectively assist in guiding the need for ICA among high-risk ACS patients, potentially reducing unnecessary procedures but further clinical studies to refine AI's role in clinical decision-making are required.ChatGPT's decision as per ICA's results