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RATIONALE AND OBJECTIVES The clinical utility of Dixon water-fat separation coronary MR angiography (CMRA) with compressed sensing (CS) reconstruction has not been determined in a patient population. This study was designed to evaluate the performance of 3.0 T non-contrast-enhanced Dixon water-fat separation CS whole-heart CMRA sequence in vitro and in vivo. MATERIALS AND METHODS In vitro phantom MRI, we compared key parameters of the SENSE and CS images. And in this prospective in vivo study, from November 2019 to October 2020, 94 participants were recruited for 3.0 T non-contrast-enhanced Dixon water-fat separation CS whole-heart CMRA. The accuracy of CMRA for detecting a ≥ 50% reduction in diameter was determined using X-ray coronary angiography (CA) as the reference method. RESULTS Compared with SENSE, CS with an appropriate acceleration factor offers both higher SNR/CNR (p < 0.05) and a shortened acquisition. Fifty-eight patients successfully completed the CMRA and CA. The sensitivity, specificity, positive predictive values, negative predictive values, and accuracy of 3.0 T non-contrast-enhanced Dixon water-fat separation CS whole-heart CMRA according to a patient-based analysis were 96.4%, 66.7%, 73.0%, 95.2% and 81.0%, respectively. The area under the receiver-operator characteristic (ROC) curve (AUC) of 3.0 T non-contrast-enhanced Dixon water-fat separation CS whole-heart CMRA for detecting significant coronary artery stenosis is 0.908, 0.895, and 0.904 in patient-, vessel-, and segment-based analyses respectively. CONCLUSION 3.0 T non-contrast-enhanced Dixon water-fat separation whole-heart CMRA using appropriate CS is a promising noninvasive and radiation-free technique to detect clinically significant coronary stenosis on patients with suspected CAD.