A 17-year-old female with sickle cell disease status post a recent stem cell transplant and on tacrolimus developed an acute expressive aphasia, dysphagia, and drooling. Brain MRI revealed diffuse restricted diffusion involving the bilateral corona radiata and areas of white matter in the right cerebral hemisphere most consistent with toxic leukoencephalopathy. Tacrolimus serum concentration was high at 19.3 ng/ml (ref 9-12 ng/ml) for which tacrolimus was discontinued. She was neurologically back at baseline 2 days later with the tacrolimus level improving to 8.2 ng/mL. Following discontinuation and the declining trend of her tacrolimus levels the patient returned to her neurologic baseline and was subsequently switched to mycophenolate mofetil for GVHD immunosuppression.