Abstract.Research into the evasion of drug resistance and adverse effects is highly significant and urgent in the clinic. Therefore, accumulating studies have focused on the development of novel target-specific molecules related to drug resistance, and the establishment of rational therapeutic approaches. Currently, studies have shown that NF-κB activation may play an essential role in the development of chemotherapy resistance in carcinoma cells. Paeoniflorin, a principal bioactive component of the root of Paeonia lactiflora Pall., has been reported to exhibit various pharmacological effects. In the present study, we reported for the first time that paeoniflorin at non-toxic concentrations may effectively modulate multidrug resistance (MDR) of the human gastric cancer cell line SGC7901/vincristine (VCR) via the inhibition of NF-κB activation and, at least partly, by subsequently downregulating its target genes MDR1,