Hydrocortisone (HC) reduced the macrophage content of four murine tumors to less than half of control values. Since HC causes monocytopenia and inhibits the recruitment of mononuclear phagocytes at sites of inflammation but does not affect the viability and proliferative capacity of macrophages, this finding suggests that the maintenance of macrophage levels in growing tumors is in part dependent upon the entry into the neoplasm of circulating monocytes. HC inhibited the growth of these tumors. The effect of HC was most marked on the mFS6 and MN/MCA1 sarcomas and 3LL carcinoma, with only marginal inhibition in the M109 carcinoma. HC augmented spontaneous and/or artificial (i.v.) metastasis in these tumor models. Cells from metastatic foci of the mFS6 sarcoma and M109 carcinoma inoculated i.m. were as susceptible to HC as cells from primary tumors. The effects of HC on macrophage content, growth and metastasis of the M109 carcinoma and mFS6 sarcoma were similar in mice with defective T-cell function (nude or thymectomized) or defective NK activity (beige or antiasialo GM1-treated) and in controls. The in vitro growth of the mFS6 and MN/MCA1 sarcomas was not modified by HC. Some inhibition of tumor-cell proliferative capacity was observed with the 3LL and M109 tumors. Tumor cell had high-affinity binding sites for glucocorticoid hormones, but these were not correlated to susceptibility in vivo. Thus it is unlikely that a direct interaction of HC with tumor cells accounts for the inhibition of tumor growth observed in vivo. To evaluate whether HC affected tumor growth by reducing the macrophage content of tumors, mFS6 sarcoma cells were transplanted, mixed with peritoneal macrophages into normal or HC-treated mice. Macrophages did not affect the growth of tumor cells in normal mice, whereas in HC-treated animals lesions from mixtures of macrophages and sarcoma cells appeared earlier and weighed more than those from tumor cells alone or tumor cells and thymocytes. However, macrophages did not reconstitute growth of the other sarcoma (MN/MCA1) in HC-treated mice. These results are consistent with the hypothesis that HC inhibited growth of some poorly immunogenic transplanted murine tumors, at least in part, by interfering with the macrophage levels in neoplastic tissues, tumor-associated macrophages providing the conditions for optimal tumor-cell proliferation at least in some neoplasms.