We investigated the mechanisms involved in the resistance to cell death observed in epithelial cancers. Here, we identify thatprimary epithelial cancer cells from colon, breast and lung carcinomas express high levels of the antiapoptotic proteins PED,cFLIP, Bcl-xL and Bcl-2. These cancer cells produced interleukin-4 (IL-4), which amplified the expression levels of theseantiapoptotic proteins and prevented cell death induced upon exposure to TRAIL or other drug agents. IL-4 blockade resulted ina significant decrease in the growth rate of epithelial cancer cells and sensitized them, both in vitro and in vivo, to apoptosisinduction by TRAIL and chemotherapy via downregulation of the antiapoptotic factors PED, cFLIP, Bcl-xL and Bcl-2.Furthermore, we provide evidence that exogenous IL-4 was able to upregulate the expression levels of these antiapoptoticproteins and potently stabilized the growth of normal epithelial cells rendering them apoptosis resistant. In conclusion, IL-4 actsas an autocrine survival factor in epithelial cells. Our results indicate that inhibition of IL-4/IL-4R signaling may serve as a noveltreatment for epithelial cancers.