A group of eight monoclonal antibodies directed against different monomorphic determinants of HLA-class II molecules was used to investigate the distribution of HLA-DC/DS/MB, -DR and -SB-like antigens on normal and pathological lymphoid and nonlymphoid tissues of human adult and fetal donors. HLA-MB/DC/DS-like molecules, as defined by the antibody TU 22, showed the most limited distribution as they were detected on B-lymphocytes, monocyte/macrophage subpopulations and distinct interstitial cells of various organs. HLA-DR and -SB-like antigens characterized by the other anti-HLA-class II reagents (TU34, TU35, TU37, TU39, TU43, TU58) were also present on these cell types. However, selective expression of HLA-DR and/or -SB like molecules was demonstrated with these antibodies on certain vascular endothelia, as well as different B-cell lymphomas and distinct epithelial cells in adults. Exclusive reactivity of the antibody TU39 shown on endothelial cells of fetal liver and kidney suggested specific functions of HLA-SB antigens during ontogeny. Furthermore, HLA-DR and/or -SB like molecules but not TU22+ HLA-DC/MB antigens were found to be inducible on normally Ia-like antigen negative epithelial cells of various diseased organs. Implications of this differential tissue distribution of HLA-DC/MB/DS, -DR and -SB like products in relation to organ transplantation, regulation of immune responses and cell differentiation are discussed.