OBJECTIVE: To determine whether sirolimus therapy is associated with neurologic complications, including stroke, among heart transplant recipients. PATIENTS AND METHODS: We retrospectively studied patients who underwent heart transplant at Mayo Clinic's site in Rochester, MN, from January 1, 1988, through June 30, 2006. RESULTS: Of 313 patients in the cohort, the medical regimen in 116 patients (37%) was switched from cyclosporine-based therapy to sirolimus. The hazard ratio of sirolimus for any neurologic or psychiatric event was 1.94 (95% confidence interval, 0.67-4.29). This hazard ratio was driven mainly by the association between sirolimus and the development of tremor and depression. Cerebrovascular events occurred with a cumulative incidence of 14% but did not occur in any of the patients who received sirolimus therapy. There were no cases of posterior reversible encephalopathy syndrome with sirolimus use. CONCLUSION: No early or late episodes of major neurotoxicity occurred in heart transplant recipients using sirolimus immunosuppression. The absence of stroke and transient ischemic attacks in these high-risk transplant recipients treated with sirolimus is notable but needs confirmation in future studies.