Thymic lesions were studied in 35 patients with fatal infectious mononucleosis (FIM) including 21 males with the X-linked lymphoproliferative syndrome (XLP) and 14 non-XLP patients. Six patterns based on the lymphocyte content and status of Hassall's bodies were observed: massive lymphoproliferation effaced the architecture and Hassall's bodies (HB) in 6 cases. Epstein-Barr virus (EBV)-laden B cells surrounded by cytotoxic T cells and natural killer cells were found in one of these cases. Only 5 of the 35 thymuses contained normal-appearing HB. Seven showed a moderate reduction in HB. Rarely, multinucleated giant cells and hyaline globules were seen where one might expect HB to reside. Plasma cells and macrophages were generally abundant. Eight displayed a marked depletion of HB. In 7, no HB were recognized. Massive necrosis was seen in one of these cases. Stress involution was encountered in only two patients, both of whom had sporadic fatal IM. Thymic lesions and alterations were similar but less extensive in sporadic FIM. These morphological studies, taken in context with clinical and experimental reports, suggest that destruction of thymic epithelium may contribute to the progression of immune defects seen in XLP following EBV infection. The destruction of HB that we observed was similar in appearance to lesions in several other immune deficiency disorders.