Interleukin-6 (IL-6) is a multifunctional cytokine that plays important roles in the immune system, hematopoiesis, and acute phase reactions. Transforming growth factor-beta (TGF-beta) also has pleiotropy including the production of acute phase proteins in hepatocytes. To elucidate the cross-talk between IL-6 and TGF-beta signaling pathways in hepatic cells, we investigated the effects of TGF-beta on IL-6-induced signal transducer and activator of transcription-3 (STAT3) activation in a human hepatoma cell line, Hep3B. IL-6-induced activation of STAT3 activity and STAT3-mediated gene expression were augmented by TGF-beta in Hep3B cells. We provide evidence that these activities were due to physical interactions between STAT3 and Sma- and MAD-related protein-3, bridged by p300. These results demonstrate a molecular mechanism of a cross-talk between STAT3 and TGF-beta signaling pathways in hepatocytes.