Objective: To study central nervous system infections after heart transplantations. Design: Retrospective cohort study. Setting: Cardiac Transplant Program at Mayo Clinic, Rochester, Minnesota. Patients: Three hundred fifteen consecutive patients who underwent heart transplantation from January 1988 through June 2006. Results: Central nervous system infections developed in 8 patients (3%), all of whom presented within the first 4 years after transplantation. The most common presentations were acute or subacute confusion or headache (88%), often without the classic symptoms of fever and neck stiffness. Direct cerebrospinal fluid examination was unrevealing in most cases, though cerebrospinal fluid protein levels were elevated in all patients with infections. Diagnoses included cryptococcal meningitis (n=3), progressive multifocal leukoencephalopathy (n=2), varicellazoster virus encephalitis (n=2), and Aspergillus fumigatus infection (n=1). Three of 8 patients died (38%) and 2 (25%) survived with mild sequelae. Central nervous system infection was a significant predictor of mortality (hazard ratio, 4.39; 95% confidence interval, 1.72-11.18; P=.002). Conclusions: Central nervous system infections are rare but devastating complications of heart transplantations. Recognition of these infections is difficult owing to a paucity of clinical manifestations. We report here, for the first time, varicella-zoster virus central nervous system infection in heart transplantations.