In order to investigate the natural history of so-called "Lennert's lymphoma" and to reevaluate whether non-Hodgkin's lymphoma with a high content of epithelioid histiocytes represents a clinicopathologic entity, we reviewed the histopathologic and clinical features of 60 patients in whom pretreatment diagnostic tissues had shown a diffuse and florid epithelioid histiocytic reaction identical to that originally described by Lennert and Mestdagh. Our study indicates that so-called "Lennert's lymphoma" is a heterogeneous group of disorders, which, in our series, included Hodgkin's disease (27 patients), non-Hodgkin's lymphoma (24 patients), angioimmunoblastic lymphadenopathy (1 patient), and atypical lymphoepithelioid cell proliferations of uncertain etiology and pathogenesis (8 patients). Most of the patients with Hodgkin's disease had Stage I or II disease without B symptoms, whereas patients with non-Hodgkin's lymphoma usually had Stage III or IV disease, commonly with B symptoms. The median survival was 79 months in the Hodgkin's disease group, compared with 12 months in patients with non-Hodgkin's lymphoma (P less than 0.0001). In patients with atpical lymphoepithelioid cell proliferations, the survival pattern was unpredictable, and the number of patients was too small for a meaningful statistical comparison. Progression to malignant lymphoma in 1 of the 8 patients with atypical lymphoepithelioid cell proliferations, however, underscores the malignant potential of this disorder. One patient with angioimmunoblast lymphadenopathy had generalized disease and constitutional symptoms. In Hodgkin's disease with a prominent epithelioid histiocytic reaction, the gross and microscopic features were similar to those observed in Hodgkin's disease in which this reaction was lacking. In non-Hodgkin's lymphoma, however both the macroscopic and microscopic features differed from those of the usual non-Hodgkin's lymphomas. Moreover, subdivision into poorly differentiated lymphocytic, mixed, and histiocytic types did not reveal any differences in median survival among these subtypes. Non-Hodgkin's lymphoma with a multifocal epithelioid histiocytic reaction previously included in the heterogeneous group called "Lennert's lymphoma" appears to be a distinct clinicopathologic entity.