The oncogenic ras mutation is a common and critical step in gastrointestinal carcinogenesis. In a previous study, we demonstrated that oncogenic ras activated the EGF-related peptide autocrine loop and that the apoptosis resistance observed in the oncogenic ras-stimulated cell (IEC-ras cell) was dependent on this activated EGF-related peptide autocrine loop. STATs (signal transducers and activators of transcription), first identified as intracellular signal transducers stimulated by cytokines, are known to also be activated by EGF. However, the role of STATs in the survival signal of IEC-ras cells is not clear. In the present study, we demonstrate that STAT3 is constitutively activated in ras-stimulated cells and that STAT3 activation is considerably suppressed by the EGF-specific receptor kinase inhibitor AG 1478. We also show that disruption of the STAT3 pathway by introduction of a dominant-negative STAT3 mutant abolishes the apoptosis resistance against UVC and MMC treatment observed in IEC-ras cells without affecting proliferation. Moreover, the expression of Bcl-2 and Bcl-xL, apoptosis-suppressive proteins, is reduced in dominant-negative STAT3-transfected cells. Thus, STAT3 appears to be an important mediator of the antiapoptotic signal in IEC-ras cells.