The CD21 antigen has been described to represent CR2, the receptor for the complement fragment C3d and also the receptor for the Epstein-Barr virus (EBV). Monoclonal antibodies B2, HB5, and B-ly4 belong to the CD21 cluster, recognizing different epitopes of the CD21-molecule. Immunohistology of lymphoid tissues employing these antibodies showed the known staining of B cells and dendritic reticulum cells. Surprisingly, B2, but not HB5 or B-ly4, stained a distinct spot in the cytoplasm of a major proportion of medullary thymocytes, in almost all peripheral blood lymphocytes, and in a substantial amount of cells in T-cell areas of peripheral lymphoid tissues. This distinct cytoplasmic B2 staining was confirmed by immuno-electronmicroscopy. A similar B2+ cytoplasmic dot was observed in B-lymphoblastic lymphomas. Staining of non-lymphoid tissues showed reactivity with all three CD21 mAb with epithelial cells of skin, lung, esophagus, jejunum, colon, pancreas, tonsil, adrenal cortex, renal tubuli, and parotid glands, and with hepatocytes and tongue muscle. In addition, endothelial cells of small vessels showed B2 staining. One possible explanation for our results is, that apart from the presence of B cells and follicular dendritic cells, a CD21-molecule may be expressed by other cell types. However, a maybe more likely explanation may be that the recognized epitopes are not exclusively associated with the C3d/EBV-receptor, but also with other structures. In particular should the possibility be recognized of cross-reactivity with CR2-related proteins, encoded by the large gene family, to which CR2 belongs.