Acute tumor lysis syndrome (ATLS) is a well-recognized complication of systemic chemotherapy for rapidly proliferating neoplasms. ATLS has rarely occurred after intrathecal chemotherapy for the treatment of leukemia with meningeal involvement. Here, we report a case of fatal ATLS complicating intrathecal injections of methotrexate, cytarabine and hydrocortisone for acute lymphoblastic leukemia which relapsed with meningeal involvement after allogeneic stem cell transplantation. This case indicates that intrathecal chemotherapy alone may be sufficient to induce ATLS. Close monitoring and prevention of ATLS are also warranted following intrathecal chemotherapy alone.