CASE PRESENTATION: A 61-year-old male with a history of seizures was transferred from another hospital for obscure gastrointestinal (GI) bleeding. Three weeks earlier, he presented with left sided weakness and epigastric pain. Evaluation revealed persistent fevers, hepatosplenomegaly, pancytopenia, a right frontal lobe lesion and a ferritin level of 43,000 ng/mL. A bone marrow biopsy (BMBx) was concerning for HLH. He was treated with steroids and etoposide for HLH and broad spectrum antibiotics for neutropenic fever. Hospital course was complicated by recurrent hematochezia requiring frequent blood product transfusions and he was transferred to our facility for further evaluation. Upon arrival, he was sedated and mechanically ventilated. Neurological exam revealed expressive aphasia and left sided weakness. Small bowel enteroscopy showed a jejunal stricture with diffuse ulceration and bleeding. Biopsy showed necrosis and inflammation without evidence of malignancy. Soluble IL-2 receptor was 6280 pg/mL. EBV serum PCR was 11,800 copies/mL. The working diagnosis was EBV associated HLH. We repeated BMBx and reviewed the outside BMBx; both showed increased histiocytes but no hemophagocytosis. MRI of the brain showed a demyelinating frontal lobe lesion. Cerebrospinal fluid PCR for JC virus was negative. Brain biopsy confirmed PML with positive tissue staining for papovavirus and in-situ hybridization for JC virus. The family decided to pursue hospice care and the patient passed away one week after discharge.