Background: Breast cancer cells can develop chemoresistance after prolonged exposure to cytotoxic drugs due to expression of the multi drug resistance (MDR) 1 gene. Type 2 cyclo-oxygenase (COX-2) inhibitors reverse the chemoresistance phenotype of a medullary thyroid carcinoma cell line, TT, and of a breast cancer cell line, MCF7, by inhibiting MDR1 expression and P-gp function.Aim: investigate the role of prostaglandin (PG) in modulating chemoresistance in MCF7 cells and to explore the involved intracellular mechanisms.Methods: native and chemoresistant MCF7 cells were treated with PGH2 and resistance to Doxorubicin was tested in the presence or absence of COX-2 inhibitors.Results: PGH2 restores resistance to the cytotoxic effects of Doxo, with concomitant nuclear translocation of the transcription factor NF-κB.Conclusions: COX-2 inhibitors prevent chemoresistance development in breast cancer cells by inhibiting P-gp expression and function by a mechanism that involves PGH2 generation and NF-κB activation.