BACKGROUND This study aimed to determine the ability of multimodality intraoperative neurophysiologic monitoring, including somatosensory evoked potentials (SSEP) and EEG, to predict perioperative clinical stroke and stroke-related mortality after open-heart surgery in high-risk patients. METHODS The records of all consecutive patients who underwent coronary artery bypass grafting, and cardiac valve repair/replacement with high risk for stroke who underwent both SSEP and EEG recording at the University of Pittsburgh Medical Center between 2009 and 2015 were reviewed. Sensitivity and specificity of these modalities to predict in-hospital clinical strokes and stroke-related mortality were calculated. RESULTS A total of 531 patients underwent open cardiac procedures monitored using SSEP and EEG. One hundred thirty-one patients (24.67%) experienced significant changes in either modality. Fourteen patients (2.64%) suffered clinical strokes within 24 hours after surgery, and eight patients (1.50%) died during their hospitalization. The incidence of in-hospital clinical stroke and stroke-related mortality among patients who experienced a significant change in monitoring compared with those with no significant change was 11.45% versus 1.75%. The sensitivity and specificity of significant changes in either SSEP or EEG to predict in-hospital major stroke and stroke-related mortality were 0.93 and 0.77, respectively. CONCLUSIONS Intraoperative neurophysiologic monitoring with SSEP and EEG has high sensitivity and specificity in predicting perioperative stroke and stroke-related mortality after open cardiac procedures. These results support the benefits of multimodality neuromonitoring during cardiac surgery.