Histiocytic cells with S100 protein compose a cell lineage independent of the monocyte‐macrophage system. Langerhans cells and indeterminate cells in the skin and oral mucosa, interdigitating cells in the T‐zone of the lymph node, and other lymphoid tissues belong to this cell lineage. In addition to these cells, small S100+cells showed morphological transition to large histiocytes. In human fetuses, a large number of S100+lysozyme‐NCA+cells first appeared in the thymic medulla by the end of the third month of gestation, and rapidly disseminated to the various lymphoid organs in accordance with the spread of T‐lymphocytes during the fourth month of gestation. S100+ small cells were more frequent than large cells and showed more rapid dissemination in the early stage. S100‐ lysozyme+NGA+immature macrophages appeared in the liver, spleen, lymph node anlage, and other tissues at the second month of gestation, and their distribution was completely different from S100+histiocytes. Fetal development of T‐zone histiocytes with S100 protein supported the hypothesis that there are two histiocytic cell lines; one is the monocyte‐macrophage system, another is the S100+T‐zone hi