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Although rare, both central nervous system and pericardial involvement of myeloma have been well described in the literature. Their simultaneous occurrence in relapsed disease, however, has not been previously reported. This case describes a 54-year-old female who was treated for high-risk multiple myeloma with multiregimen chemotherapy and allogeneic hematopoietic stem cell transplantation. Four months after transplant, she was found to have relapsed disease manifesting as an extraosseous, intracranial plasmacytoma and simultaneous malignant pericardial effusion. Her disease characteristics, treatment course, radiologic and pathologic findings are described in detail, and we review the previous literature to determine the various aspects of her disease that may have contributed to her aggressive clinical course.