Background. There is enough evidence to support the knowledge that multicentric reticulohistiocytosis (MR) is a histiocytic proliferative disorder; however, the type of histiocytes involved is not well established.

Objective and Methods. To study the nature of cells present in MR lesions by studying the immunohistochemical profile of three new cases and reviewing 23 cases reported in the literature.

Results. MR histiocytic cells are positive for vimentin, CD68, and CD45, negative for S-100 protein, CD34, and XIIIa factor, and weak reactors for thrombomodulin. Small activated histiocytes are MAC387 positive. Lymphocytes, mainly CD4+ cells, are found in MR infiltrates.

Conclusions. The MR immunophenotypic pattern does not suggest a type I or type II dendrocyte or a Langerhans cell origin. On the other hand, it points to a different cell derived from the monocyte-macrophage line. CD4+ cells may be responsible for activating the proliferation of histiocytic cells. Small histiocytic MAC387+ cells are likely to become the MR multinucleated giant cells.