The cytokines, IL-1 beta, TNF-alpha, IL-6, IL-11, leukemia inhibitory factor, and ciliary neurotrophic factor, stimulate the expression of specific sets of acute phase plasma proteins in the rat hepatoma H-35 cell line. In this paper, the experimental drug suramin is shown to inhibit in a dose-dependent fashion the cell response to these cytokines, with the exception of TNF-alpha. The action of the IL-6-type cytokines is more sensitive to suramin inhibition that that of IL-1 beta. The effect of suramin is detectable within 30 min at the level of gene transcription and appears to be mediated by the impairment of receptor function and/or signal transduction, rather than by the inhibition of nucleic acid polymerases or DNA topoisomerase II. Similar analysis of human hepatoma HepG2 cells indicated a several-fold higher resistance to suramin and in inhibition that was less cytokine-specific than in H-35 cells. The data suggest that suramin has the potential not only to modulate the proliferation or differentiation of tumor cells as described previously, but also to affect a differentiated cell function. This broad pleiotropic action has to be taken into consideration when applying suramin as a therapeutic agent.