Glucocorticoids are known to be potent regulators of inflammation and have been used pharmacologically against inflammatory, immune, and lymphoproliferative diseases for more than 50 years. Due to their possible and well‐documented side effects, it is crucial to understand the molecular mechanisms and targets of glucocorticoid action in detail. Several modes of action have been discussed; nevertheless, none of them fully explain all the functions of glucocorticoids. Therefore, we analyzed the cross‐talk between glucocorticoids and interleukin‐6 (IL‐6) in the liver. IL‐6 exerts pro‐inflammatory as well as anti‐inflammatory properties and is a main inducer of the acute‐phase response. The balance between the proinflammatory and anti‐inflammatory activities of IL‐6 is tightly regulated by suppressor of cytokine signaling 3 (SOCS3), a well‐known feedback inhibitor of IL‐6 signaling. Here, it is demonstrated that glucocorticoids enhance IL‐6–dependent γ‐fibrinogen expression. Studying of the underlying mechanism revealed prolonged activation of signal transducer and activator of transcription 3 (STAT3) caused by down‐regulation of SOCS3 protein expression. Consequently, in SOCS3‐deficient cells glucocorticoids do not affect IL‐6–induced signal transduction. Moreover, in hepatocytes lacking the SOCS3 recruiting motif within gp130, IL‐6–dependent γ‐fibrinogen expression is not influenced by glucocorticoid treatment. Conclusion: Glucocorticoids interfere with IL‐6–induced expression of the feedback inhibitor SOCS3, thereby leading to enhanced expression of acute‐phase genes in hepatocytes. This mechanism contributes to the explanation of how glucocorticoids affect inflammation and acute‐phase gene induction. (HEPATOLOGY 2012;55:256–266)