The CD4 antigen is expressed on T cells of all mammalian species examined and appears to play an important role in the response of T cells to antigen. In humans, the molecule acts as a receptor for the AIDS virus. Previous studies have demonstrated that M phi in the rat and human also express the CD4 antigen, which is indistinguishable from that on T cells. In this paper we demonstrate by FACS analysis, Northern blot hybridization, and immunoperoxidase labeling that, in striking contrast to the rat and human, mouse M phi do not express the CD4 (L3T4) antigen. This species heterogeneity indicates that T cells and M phi regulate CD4 antigen expression independently and that CD4 may not be essential for M phi function.