Although grayscale intravascular ultrasound (IVUS) is commonly used for assessing coronary lesion morphology and optimizing stent implantation, detection of vulnerable plaques by IVUS remains challenging. We aimed to develop machine learning (ML) models for predicting optical coherence tomography-derived thin-cap fibroatheromas (OCT-TCFAs).In 517 patients with angina, 414 and 103 coronary lesions were randomized into training vs. test sets. Each of the IVUS-OCT co-registered frames (including 32,807 for training and 8101 for test) was labeled according to the presence vs. absence of OCT-TCFA. Among 1449 computed IVUS features based on two-dimensional geometry and texture, 17 features were finally selected and used in supervised ML with artificial neural network (ANN), support vector machine (SVM), and naïve Bayes.IVUS sections with (vs. without) OCT-TCFA showed a larger plaque burden, and a smaller and eccentric lumen. TCFA-containing sections were characterized by increased ratios of variance, entropy, and kurtosis; reduced ratio of homogeneity within the superficial to the deeper plaque; and decreased smoothness within the fibrous cap. In addition, OCT-TCFA was associated with low ratios of gamma-beta, Nakagami-μ and Nakagami-ω, and a high ratio of Rayleigh-b within the superficial to the deeper region. With a 5-fold cross-validation, the averaged accuracies were 81 ± 5% for ANN (area under the curve [AUC] = 0.80 ± 0.08), 77 ± 4% for SVM (AUC = 0.74 ± 0.05), and 78 ± 2% for naïve Bayes (AUC = 0.77 ± 0.04) for predicting OCT-TCFA. In the test set, ANN and naïve Bayes showed the overall accuracies of >80%.Supervised ML algorithms with computed IVUS features predicted the presence of OCT-TCFA. This data-driven approach may help clinicians in recognizing high-risk coronary lesions.