Hematopoietic malignancies are the most commonly reported neoplasms in lizards, occurring sporadically as in other reptiles. An unusually high incidence of lymphoid neoplasia occurred in a collection of Egyptian spiny-tailed lizards (Uromastyx aegyptius) from 1993–2001. Eight of 15 lizards necropsied at the Louisville Zoological Garden (53%) had multicentric lymphoma. Immunohistochemistry was not useful in characterizing the lineage of normal or neoplastic lymphocytes. By light and electron microscopy (EM), the neoplasms had plasmacytoid morphologic features suggesting B-cell origin, although some tumors also had a primitive lymphoblast component. A concurrent leukemic blood profile was identified in seven of the cases (88%). All were adult animals and no sex predilection was observed. No exposure to exogenous carcinogens was observed. Some of the lizards were unrelated, so hereditary factors were unlikely. Although examination by EM and viral isolation performed on archived tissues and plasma failed to detect viruses, an infectious etiology still warrants consideration.