The cell surface antigenic phenotype of 18 cases of central nervous system (CNS) large-cell lymphoma (14 primary, four secondary) was examined by an immunoperoxidase technique using antibodies that identify B cell restricted and associated antigens. All cases were shown to be of B cell origin by virtue of the expression of monotypic immunoglobulin (Ig) (16 IgM, two IgG) and the pan B cell antigen B1 (CD20). A panel of monoclonal antibodies directed against B cell restricted and associated activation antigens including B5, Blast-1, Blast-2 (CD23), BB1, interleukin 2 receptor (IL2R, CD25), T9 (transferrin receptor) and TNK-TAR (4F2) was used on 12 of the cases. The majority expressed T9 and TNK-TAR. Blast-1 was expressed by less than half the cases and Blast-2 and B5 by one of 12 cases each. This is in contrast to 10 non-CNS diffuse large cell lymphomas where B5 and Blast-1 were present on all cases. This study confirms previous observations that primary CNS large cell lymphomas are of B cell derivation. Moreover, the differences in expression of B cell activation antigens on CNS large cell lymphomas as compared to non-CNS lymphomas raise the possibility that a subset of neoplastic B cells may have unique tropism for the CNS.