Here we have investigated whether inhibition of c‐Fos expression in RKO human colon carcinoma cells (HCCCs) would result in reduced TGFβ1 expression and suppression of tumor growth in athymic mice. We stably transfected RKO cells with c‐Fos small interfering RNA (siRNA) or with the corresponding control siRNA. Using these stable cell lines, we demonstrated that siRNA‐c‐Fos significantly suppressed both AP‐1 binding, promoter reporter activity at the proximal AP‐1 site in the TGFβ1 promoter, and TGFβ1 production. Further, we established colon cancer xenografts with each of RKO‐siRNA‐EV, RKO‐siRNA‐Ctrl and RKO‐siRNA‐c‐Fos cells. By 24 days, the tumor size of RKO‐siRNA‐c‐Fos xenografts was 40% that of either RKO‐EV or RKO‐siRNA‐Ctrl. Immunohistochemistry (IHC) of tumor xenografts demonstrated that siRNA‐c‐Fos significantly blocked c‐Fos expression, and consequently expression of TGFβ1. However, expression of TGFβ2 and TGFβ3 were unaffected. Overall, our results demonstrate that blockade of TGFβ1 production by siRNA‐c‐Fos effectively suppressed tumor growth in vivo.