Many human tumors harbor persistently-active Signal Transducer and Activator of Transcription (ST AT)3 protein. There is substantial evidence that aberrantly-active STAT3 is a master regulator of events that promote carcinogenesis and human tumor formation. Abnormal STAT3 activity induces uncontrolled growth and survival of cells, thereby contributing to neoplastic transformation and progression. Cisplatin is a major chemotherapeutic modality for ovarian cancer, but is frequently challenged by drug resistance. Given that STAT3 is aberrantly-active in many human tumors, including ovarian cancer, there is the potential that it contributes to the development of Cisplatin resistance, a problem ripe for investigation. This study was conducted to explore the potential that the aberrant STAT3 present in ovarian cancer cells contributes to the decreased sensitivity to Cisplatin observed for ovarian cancer cells. The investigation revealed that STAT3 is aberrantly activated in cancer cell lines resistant to Cisplatin, but not in sensitive cells. Inhibition of aberrant STAT3 activity by the small-molecule STAT3 inhibitor, NSC 74859, increased growth inhibition induced by Cisplatin in resistant ovarian cancer cells. Furthermore, NSC 74859 enhanced apoptosis induced by Cisplatin in resistant cells in vitro by nearly 52%. Collectively, these observations indicate that inhibition of hyperactive STAT3 increases Cisplatin sensitivity, and therefore effectiveness, in resistant cells. Thus, STAT3 represents a viable target for enhancing the sensitivity of ovarian cancer cells to Cisplatin.