Non-small cell lung cancer (NSCLC) is highly resistant to chemotherapy and radiation. Because these treatments induce apoptosis, efforts are underway to define molecular events opposing cell death in NSCLC cells. The transcription factor Stat3 was reported recently to promote growth of several human NSCLC cell lines, including A549. Because Stat1 and Stat3 often elicit opposite effects, we assessed whether Stat1 would couple to A549 cell apoptosis. Interferon-gamma (IFN-gamma) markedly induced Jak1 and Stat1 activation in cells cultured under optimal growth conditions. IFN-gamma also activated Stat3. IFN-gamma inhibited proliferation but did not induce apoptosis; however, IFN-gamma synergized with activation of Fas to induce apoptosis, as indexed by cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP), as well as DNA laddering. Knockdown of Stat1 or Stat3 with small interfering RNA (siRNA), separately or together, did not inhibit apoptosis, although a paninhibitor of Jak1 did. Our findings suggest that the proapoptotic actions of IFN-gamma in A549 cells occur downstream of Jak1 activation by a noncanonical pathway that does not involve the Jak1 target, Stat1.