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Aim: To investigate the mechanism of reversing resistance of a hepatic carcinoma multidrug-resistant cell BEL-7402/5-FU with parthenolide (PTL). Materials & methods: BEL-7402/5-FU cells were treated with different concentrations of PTL and/or 5-fluorouracil. The proliferation inhibition rates, NF-κB, P-glycoprotein, MRP, Bcl-2, WNT1 and p53 levels were determined. Results: The results showed that PTL did not only have proliferation inhibition influence on BEL-7402/5-FU in a concentration-dependent manner, but also significantly increased the proliferation inhibition role of 5-fluorouracil on BEL-7402/5-FU, to reverse the resistance of hepatic carcinoma-resistant cells. PTL could also inhibit the NF-κB activity and the expression of P-glycoprotein, MRP, Bcl-2 and WNT1, and increase the expression of p53. Conclusion: Our research suggests that clinical administration of PTL may be useful for hepatic carcinoma patients.