X‐linked lymphoproliferative disease is characterized by immune dysregulation and uncontrolled lymphoproliferation on exposure to Epstein–Barr virus (EBV). This disease has been attributed to mutations in the SAP gene (also denominated as SH2D1A or DSHP). To delineate the role of SAP in the pathophysiology of X‐linked lymphoproliferative disease, a strain of sap‐deficient mice has been generated by deleting exon 2 of the gene. After infection with murine gammaherpesvirus‐68, which is homologous to EBV, the mutant mice exhibit more vigorous CD8⁺ T cell proliferation and more disseminated lymphocyte infiltration compared to their wild‐type littermates. Chronic tissue damage and hemophagocytosis were evident in sap‐deficient mice but not in their wild‐type littermates. Concordantly, murine gammaherpesvirus‐68 reactivation was observed in sap‐deficient mice, indicating an impaired control of the virus. Notably, IgE deficiency and decreased serum IgG level were observed in mutant mice prior to and after murine gammaherpesvirus‐68 infection, which reproduces hypo‐gammaglobulinemia in X‐linked lymphoproliferative disease patients. This mouse model will therefore be a useful tool for dissecting the various phenotypes of X‐linked lymphoproliferative disease. J. Med. Virol. 71:446–455, 2003. © 2003 Wiley‐Liss, Inc.