Male patients with the X-linked lymphoproliferative syndrome (XLP) have an inherited immune deficiency to Epstein-Barr virus (EBV) infection that results in fatal infectious mononucleosis (IM), acquired hypogammaglobulinemia- or agammaglobulinemia, virus-associated hemophagocytic syndrome, and non-Hodgkin's malignant lymphoma (ML). A clinicopathologic analysis of 17 patients with XLP who developed ML was performed. The median age of the patients at the time of diagnosis was 4.0 years (range, 2-19 years). The median overall survival was 12 months (range, 1-216 months). Eight patients had maternally related male relatives with ML. Other phenotypes of XLP were documented in male relatives of the remaining nine patients. Common presenting symptoms were fever, nausea, vomiting, and abdominal pain. Nine patients had "B" symptoms. All ML occurred at extranodal sites. The intestines, most commonly ileocecal, were involved in 76.5% of the cases. Thirteen patients had localized disease (Stages I and II) and four patients had advanced disease (Stages III and IV). A diffuse histologic pattern of growth was observed in all cases. The distribution of histologic subtypes included small noncleaved (41.2%), large noncleaved (17.6%), immunoblastic (17.6%), small cleaved or mixed cell (11.8%), and unclassifiable (5.9%) ML. Surgical resection, radiation therapy, and chemotherapy resulted in disease-free survivals of up to 192 months in eight patients (median 114 months; range, 12-192 months). Eight of 17 patients (47%) are still alive. A median survival of only 6.0 months (range, 1-12 months) was observed in the nine patients who died. No residual ML was found at autopsy. The small noncleaved subtype had an adverse prognosis (seven of nine deaths versus one of eight survivors; P less than 0.05). Bacterial infection was the major cause of death (seven of nine patients). Characteristics that distinguish ML in XLP from other ML include a maternal family history of XLP, early age of onset, acquired hypogammaglobulinemia, post-EBV infection, and ileocecal involvement.