Interleukin‐6 (IL‐6) is a pro‐inflammatory cytokine that plays an important role in the pathogenesis of inflammatory bowel disease. TGF‐β, a multifunctional cytokine, is a potent negative regulator of mucosal inflammation in the intestine. The aim of the present study is to determine possible cross‐talk between IL‐6 and TGF‐β signaling pathways. Model intestinal epithelial cell lines, Caco2‐BBE were used. We show that TGF‐β receptor Type II is predominantly present in the basolateral membrane of intestinal epithelial cells. TGF‐β1 induces a time‐dependent phosphorylation of Smad2 and co‐immunoprecipitation of SMAD‐2 with Smad‐4 and its subsequently translocation to the nucleus. We show that pretreatment of cells with TGF‐β1 is associated with a down‐regulation of IL‐6 induced tyrosine phosphorylation of STAT1 and STAT3 and suppression of ICAM‐1 expression. Furthermore, TGF‐β1 pretreatment resulted in a significant inhibition of IL‐6 induced ICAM‐1 promoter activity. TGF‐β mediated inhibition of IL‐6 induced ICAM‐1 expression was reversed by transfection with dominant negative Smad2 constructs. In conclusion, we show that: 1) TGF‐β receptor Type II is predominantly located on basolateral membrane and receptor stimulation activates Smad pathway; 2) TGF‐β1 down‐regulates IL‐6‐induced tyrosine phoshorylation of STAT1 and STAT3 and ICAM‐1 expression; and 3) Smad2 is required for the down‐regulation of IL‐6 signaling by TGF‐β. Collectively, our data demonstrate a cross‐talk between TGF‐β and IL‐6, and TGF‐β may play a role in the negative regulation of IL‐6 signaling in intestinal epithelial cells.