Treatment of rat hepatoma H-35 cells with purified human recombinant interleukin-11 (IL-11) resulted in the stimulated production of several major acute phase plasma proteins. The qualitative and quantitative changes were comparable to those mediated by IL-6 or leukemia inhibitor factor (LIF). Like IL-6, IL-11 acted synergistically with IL-1 on type 1 acute phase proteins. The combination of IL-11 and dexamethasone yielded a magnitude of stimulation which was more similar to the combination of LIF and dexamethasone than IL-6 and dexamethasone. IL-11 elicited in treatment of primary cultures of rat hepatocytes a qualitative change of plasma protein production which was similar to that in H-35 cells. Comparison of rat and human hepatoma cells indicated that the IL-11 response did not correlate with that of IL-6 or LIF, suggesting that the action of IL-11 was mediated by an IL-11-specific receptor system. However, the intracellular transduction of the IL-11, IL-6, and LIF signals to the acute phase protein genes seems to rely, in part, on common elements as judged from their stimulatory effects on the transfected expression vector containing the IL-6 response element of the rat beta-fibrinogen gene. The finding that IL-11 shares liver-regulating properties with IL-6 and LIF suggests that IL-11 has the potential of contributing to the control of systemic homeostasis and hepatic acute phase response.