Patients with atrial septal defect (ASD) exhibit distinctive electrocardiogram (ECG) patterns. However, ASD cannot be diagnosed solely based on these differences. Artificial intelligence (AI) has been widely used for specifically diagnosing cardiovascular diseases other than arrhythmia. Our study aimed to develop an artificial intelligence-enabled 8-lead ECG to detect ASD among adults.In this study, our AI model was trained and validated using 526 ECGs from patients with ASD and 2,124 ECGs from a control group with a normal cardiac structure in our hospital. External testing was conducted at Wuhan Central Hospital, involving 50 ECGs from the ASD group and 46 ECGs from the normal group. The model was based on a convolutional neural network (CNN) with a residual network to classify 8-lead ECG data into either the ASD or normal group. We employed a 10-fold cross-validation approach.Statistically significant differences (p < 0.05) were observed in the cited ECG features between the ASD and normal groups. Our AI model performed well in identifying ECGs in both the ASD group [accuracy of 0.97, precision of 0.90, recall of 0.97, specificity of 0.97, F1 score of 0.93, and area under the curve (AUC) of 0.99] and the normal group within the training and validation datasets from our hospital. Furthermore, these corresponding indices performed impressively in the external test data set with the accuracy of 0.82, precision of 0.90, recall of 0.74, specificity of 0.91, F1 score of 0.81 and the AUC of 0.87. And the series of experiments of subgroups to discuss specific clinic situations associated to this issue was remarkable as well.An ECG-based detection of ASD using an artificial intelligence algorithm can be achieved with high diagnostic performance, and it shows great clinical promise. Our research on AI-enabled 8-lead ECG detection of ASD in adults is expected to provide robust references for early detection of ASD, healthy pregnancies, and related decision-making. A lower number of leads is also more favorable for the application of portable devices, which it is expected that this technology will bring significant economic and societal benefits.© 2023 Luo, Zhu, Zhu, Li, Yu, Lei, Lin, Zhou, Cui, Zhu, Li, Zuo and Yang.