Abstract CD68 KP1 antigen expression in a series of 298 non-Hodgkin's lymphoma (NHL) cases, including 41 cases of CD30 Ki-1 -positive anaplastic large cell (Ki-1 + ALC) lymphomas, was examined. Among the cases in this series, 12 large cell NHLs, including five centroblastic (G group according to the Working Formulation) NHLs, three immunoblastic (H group) NHLs, and four Ki-1 + ALC lymphomas, were found to express KP1. By extensive immunophenotypic analysis and in situ hybridization, KP1-positive large cell lymphomas of the G and H groups were assigned a B-cell phenotype. The pattern of KP1 staining usually consisted of localized small to medium-sized cytoplasmic dots; only two cases showed diffuse fine granular reactivity. In two of the four Ki-1 + ALC lymphomas tumor cells failed to express a B- or T-cell phenotype and stained positively for lysozyme, whereas in the other two cases they showed a hybrid T/histiocytic, phenotypic profile. KP1 staining of Ki-1 + ALC lymphoma cells was usually intense and showed a diffuse granular cytoplasmic pattern; tumor cells also expressed the CD13 antigen and showed strong reactivity with the anti-CD68 EBM11 antibody. Our results suggest that certain subsets of large “blastic” B-cell lymphomas may simultaneously express the CD68 KP1 histiocyte-specific marker and other myeloid-associated antigens, indicating the necessity of using a multiparameter approach in the determination of cell lineage. Moreover, this study, which demonstrates that the expression of CD68 KP1 and CD30 antigens is not mutually exclusive, supports the view that a fraction of cases diagnosed as Ki-1 + ALC lymphomas (at least those with KP1 expression along with the lack of B- or T-antigen expression) represent true histiocytic lymphomas despite the Ki-1 + phenotype.