Human myelomonocytic leukemic cell line, designated as KY-821, and its sublines KY-Ra, KY-VCR, and KY-MTX, which were resistant to cytosine arabinoside, vincristine, and methotrexate, respectively, were compared for response to various hematopoietic growth factors. Cells of KY-Ra and KY-VCR proliferated in response to natural interleukin-1 (nIL-1), whereas the proliferation of KY-821 and KY-MTX was inhibited. Unexpectedly, recombinant IL-1 alpha and IL-1 beta had no effect on the proliferation of each cell line. The effect of nIL-1 was partially deleted by an addition of optimal anti-IL-1. Supernatants of each cell line had no IL-1 activity. Interferon gamma (IFN gamma) and tumor necrosis factor alpha (TNF alpha) also had an inhibitory effect for KY-821 and KY-MTX, but lacked such effect in KY-RA and KY-VCR. nIL-1, IFN gamma and TNF alpha could not differentiate between any of the cell lines but IFN gamma and TNF alpha induced monocytic surface antigens. In addition, there was no difference in the number of IL-1 and TNF alpha receptors in each cell line. These results indicate that there is a difference in biological effects between nIL-1 and recombinant IL-1 species and acquirement of resistance for some types of drugs may associate closely with different responses to hematopoietic growth factors, probably through altered postmembranous transduction.