The purpose of this study was to determine the effect of immunosuppressive drugs on the production of inflammatory cytokines and on the generation of macrophages from bone marrow precursors. Lipopolysaccharide‐stimulated peripheral blood mononuclear cells (PBMCs) were cultured in the presence of therapeutic concentrations of 6‐mercaptopurine (6‐MP), methotrexate (MTX). or prednisolone. The effect of these drugs on the expression of interleukin (IL)‐lβ, IL‐8, and tumor necrosis factor‐α (TNF‐α) was studied using bioassays and Northern analysis. The generation of monocytes/ macrophages from precursors in the bone marrow was examined by culturing murine bone marrow cells with macrophage colony‐stimulating factor (M‐CSF) in the presence or absence of these agents. 6‐MP and MTX did not inhibit the production or messenger RNA (mRNA) expression of the macrophage‐derived cytokines, although prednisolone did. Both 6‐MP and MTX substantially decreased the generation of macrophages from bone marrow precursors. We conclude that the beneficial effects of these immunosuppressive agents might be due to the suppression of the generation of monocytes in the bone marrow precursors, secondarily diminishing the production of cytokines, eicosanoids, and the production of free radicals. Copyright © 1995 Crohn's & Colitis Foundation of America, Inc.