The signal transducer and activator of transcription (STAT) proteins have been implicated in cytokine-regulated proliferation, differentiation and cell survival. Interleukin-6 (IL-6), a pleiotropic cytokine, induces a robust and sustained activation of STAT3 in M1 acute myeloid leukemia cells, which in turn undergo growth arrest, terminal differentiation and apoptosis in response to IL-6. The roles of STAT3 activation in IL-6-mediated responses in M1 cells are not fully understood. We introduced STAT3 antisense cDNA into M1 cells. STAT3 antisense cDNA blocked the expression and IL-6-induced tyrosine phosphorylation and DNA binding of STAT3, and resulted in reduction of both IL-6-induced growth arrest at G(0)/G(1) phase and macrophage differentiation in the M1 transformants. This observation is in accordance with previous reports and confirms that STAT3 plays an essential role in IL-6-induced growth arrest and terminal differentiation in M1 leukemia cells. On the other hand, STAT3 antisense cDNA augmented IL-6-induced apoptosis of M1 cells, which was supported by the cell cycle assay, DNA fragmentation assay and detection of the p17 active fragment of Caspase 3. As proliferation inhibition and differentiation induction stands for a negative signal, while survival maintenance stands for a positive signal, we conclude that STAT3 exerts two-way regulation on the biological effects of IL-6 in M1 leukemia cells.