Systemic vasculitis is an uncommon manifestation of X-linked lymphoproliferative disease (XLP), a disorder in which there is a selective immune deficiency to Epstein-Barr virus (EBV). The molecular basis for XLP has recently been ascribed to mutations within SLAM-associated protein (SAP), an SH2 domain-containing protein expressed primarily in T cells. The authors describe a patient who died as a result of chronic systemic vasculitis and fulfilled clinical criteria for the diagnosis of XLP. Sequencing of this patient's SAP gene uncovered a novel point mutation affecting the SH2 domain. The patient presented with virus-associated hemophagocytic syndrome (VAHS) and later had chorioretinitis, bronchiectasis, and hypogammaglobulinemia develop. He further developed mononeuritis and fatal respiratory failure. Evidence of widespread small and medium vessel vasculitis was noted at autopsy with involvement of retinal, cerebral, and coronary arteries as well as the segmental vessels of the kidneys, testes, and pancreas. Immunohistochemical analysis using antibodies to CD20, CD45RO, and CD8 revealed that the vessel wall infiltrates consisted primarily of CD8(+) T cells, implying a cytotoxic T-lymphocyte response to antigen. EBV DNA was detected by polymerase chain reaction (PCR) in arterial wall tissue microdissected from infiltrated vessels further suggesting that the CD8(+) T cells were targeting EBV antigens within the endothelium. The authors propose that functional inactivation of the SAP protein can impair the immunologic response to EBV, resulting in systemic vasculitis.