In the human lymphoreticular system, the α subunits of S-100 protein is found in the ordinary monocyte-macrophage lineage, and the β subunit is found in so-called T-zone histiocytes, including interdigitating reticulum cells. The β subunit is also present in some of CD8(+) T lymphocytes. In the present study, the ontogeny of these histiocytes and lymphocytes was investigated. Human yolk sacs, embryos and fetuses from the 4th to 21st weeks of gestation were examined for the presence of S-100 protein subunits by an immunohistochemical method, using antisera monospecific to each subunit. S-100α(+) histiocytes were present in yolk sacs and hepatic sinusoids by the 4th week of gestation, before bone marrow hematopoiesin had developed. As gestation proceeded, their distribution and frequency became similar to those of S-100α(+) histiocytes of the adults. No S-100β(+) cells were found in yolk sacs. S-100β(+) histiocytes were first detected in the hepatic sinusoids of 5th week embryos and later, they distributed in other lymphoid organs. S-100β(+) lymphocytes were not found in the liver and they were first detected in the thymus at the 12th week of gestation, subsequently distributing in other lymphoid organs.These results suggest that S-100β(+) lymphocytes and histiocytes may belong to different cell lineages, and that S-100β(+) lymphocytes may not be the precursors of histiocytes.