Rest-stress SPECT myocardial perfusion imaging (MPI) is widely used to evaluate coronary artery disease (CAD). We aim to evaluate stress-only versus rest-stress MPI in diagnosing CAD by machine learning (ML).A total of 276 patients with suspected CAD were randomly divided into training (184 patients) and validation (92 patients) cohorts. Variables extracted from clinical, physiological, and rest-stress SPECT MPI were screened. Stress-only and rest-stress MPI using ML were established and compared using the training cohort. Then the diagnostic performance of two models in diagnosing myocardial ischemia and infarction was evaluated in the validation cohort.Six ML models based on stress-only MPI selected summed stress score, summed wall thickness score of stress%, and end-diastolic volume of stress as key variables and performed equally good as rest-stress MPI in detecting CAD [area under the curve (AUC): 0.863 versus 0.877, P = 0.519]. Furthermore, stress-only MPI showed a reasonable prediction of reversible deficit, as shown by rest-stress MPI (AUC: 0.861). Subsequently, nomogram models using the above-stated stress-only MPI variables showed a good prediction of CAD and reversible perfusion deficit in training and validation cohorts.Stress-only MPI demonstrated similar diagnostic performance compared with rest-stress MPI using 6 ML algorithms. Stress-only MPI with ML models can diagnose CAD and predict ischemia from scar.Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.