The Src homology 2 domain protein 1A (SH2D1A) is a small, 128-amino acid protein consisting of a single SH2 domain; it is probably involved in signal regulation. It is expressed in activated T and natural killer (NK) cells, but not in B lymphocytes. It was discovered in studies on the rare hereditary condition X-linked lymphoproliferative disease (XLP). Individuals with this condition either lack or carry an altered protein. The serious symptoms (fatal mononucleosis) present almost exclusively at the first encounter with Epstein-Barr virus (EBV). The absence of SH2D1A in B cells, which are the targets of EBV, has to be reconciled with this clinical situation. In an earlier search for B lymphocytes expressing SH2D1A, we detected it in EBV-carrying type I Burkitt's lymphoma (BL) lines. We now show SH2D1A in 5 EBV-negative classical Hodgkin's disease (HD)-derived cell lines. Two lines belong to the T lineage and 3 to the B lineage. One B-HD line, which originated from nodular lymphocyte-predominant Hodgkin's lymphoma and differed in phenotype, was SH2D1A-negative. This finding is in accordance with the previously reported abundant SH2D1A mRNA in Hodgkin and Reed-Sternberg (HRS) cells. We thus found SH2D1A expression in lines of malignant origin assigned to the B lineage. Its presence in HRS cells may lead us closer to an understanding of the pathophysiology of the serious syndrome connected with EBV infection in XLP patients, because HRS-like cells have been detected in the lymphoid tissue of patients with infectious mononucleosis. It is likely therefore that in addition to the demonstrated functional defect of T and NK cells imposed by the SH2D1A mutation, the behavior of certain EBV-infected B lymphocytes is also modified.