Transcription factor decoy oligodeoxynucleotides (ODN) represent a novel tool for targeted inhibition of the STAT3 signaling pathway. To investigate its therapeutic potential in ovarian cancer, a double-stranded decoy ODN mimicking STAT3-specific cis-elements was transfected into two ovarian cancer cell lines OVCAR3 and SKOV3. The STAT3 decoy ODN treatment specifically blocked STAT3 signaling, and inhibited cell proliferation by inducing apoptosis and cell cycle arrest. These results suggest that targeted blockade of the STAT3 signaling pathway with a decoy ODN may represent a potential therapeutic approach in the treatment of ovarian cancer.