A group of 63 cases of anaplastic large cell lymphomas (variants of diffuse large cell lymphomas often diagnosed as "malignant histiocytosis") was characterized on both morphologic criteria and expression of epithelial membrane antigen (EMA) and Ki-1 antigen (CD30). On the basis of the reactivity of these tumors with anti-EMA and anti-Ki-1 antibodies, four subtypes could be distinguished. In the majority of cases (n = 49), neoplastic cells coexpressed EMA and Ki-1 antigens. Nineteen of these cases were tested for IL-2R, and all were positive (Type I, EMA+, Ki-1+, IL-2R+). In the second group (n = 5), the neoplastic cells expressed EMA but not the Ki-1 antigen. These cases were not tested for the presence of IL-2R (Type II, EMA+, Ki-1-, IL-2R?). There were tumors with similar morphology expressing only Ki-1 antigen (Type III, EMA-, Ki-1+, IL-2R-) or negative for both EMA and Ki-1 antigens (Type IV, EMA-, Ki-1-, IL-2R-). EMA appeared to occur predominantly on activated cells, as has been previously shown for Ki-1 antigen. Analysis using monoclonal antibodies to T-cell, B-cell, or macrophage-associated differentiation antigens showed that these tumors were heterogeneous in terms of cell lineage. Tumors coexpressing EMA, Ki-1, and IL-2R (Type I), were most commonly of T-cell origin (n = 12); the remainder in this type expressed B-cell markers (n = 4), a mixed B/T phenotype (n = 2), or no clear phenotype (n = 9). By contrast, tumors of Types II, III, and IV were mainly from B-cell origin (n = 6) or showed a mixed B/T phenotype (n = 1). Despite the fact that a significant proportion of these cases were initially classified morphologically as "malignant histiocytosis," only 3 of the 63 cases were possibly of histiocytic origin. These results confirm that true malignant histiocytosis is rare and that most tumors with histologic features currently regarded as being consistent with this diagnosis are lymphocytic in origin and express activation antigens such as EMA, Ki-1 antigen, and IL-2R.