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Background: Calcineurin Inhibitors (CNIs) play a pivotal role in anti rejection therapy for transplant patients. Neurotoxicity is a known side effect that usually manifests as encephalopathy but myoclonus has also been described. Perioperative myoclonus as a manifestation of neurotoxicity, has not been well studied. Methods: We retrospectively reviewed data from 842,762 patients from the Nationwide Inpatient Sample (NIS) database from January 2011 to December 2014. Of those records we compared 56,423 patients requiring CNIs and undergoing Heart Transplant (HT) with 786,339 patients undergoing Coronary Artery Bypass Graft (CABG) surgery as controls. The objective was to study the rates of myoclonus in patients undergoing cardiac surgery, especially those requiring CNIs, and study the outcome of those patients with myoclonus. The NIS database from January 2011 to December 2014 was the source for the analysis. Patients with underlying epilepsy or hypo-ischemic encephalopathy based on ICD-9-CM codes were excluded from the study. Results: A total of 147 patients (0.26%) were found to have myoclonus in the HT group versus 338 patients (0.04%) in the CABG group, p < 0.0001. No differences in the demographics were seen except for kidney disease which was higher in the HT group. The difference remained statistically significant after adjusting for confounders. Patients with myoclonus in both groups were more likely to have acute kidney injury and have a prolonged length of stay. Only patients with myoclonus in the CABG group had higher rates of discharge disposition to a nursing home and higher rates of in-Hospital mortality. A trend towards higher in-Hospital mortality was found in patients with myoclonus in the HT group. Conclusion: In this study we have compared the rate of myoclonus found in HT patients versus CABG patients. We have identified calcineurin inhibitors as potentially contributing to myoclonus due to its neurotoxic effects. The study also suggests that other disease processes like renal failure may also have an impact on the rate of myoclonus even in the absence of calcineurin inhibitors. Higher rates of myoclonus were seen in patients undergoing HT when compared to patients undergoing CABG, suggesting that CNIs may increase the risk for myoclonus. Myoclonus may be a clinical indicator of patient overall health including a more permeable blood brain barrier. In-Hospital mortality was higher in patients with myoclonus undergoing CABG and a trend towards significance in the HT group suggesting that it may be a marker of poor prognosis. More studies are needed to corroborate our findings.