Oxaliplatin is a first-line therapy for colorectal cancer, but cancer cell resistance to the drug compromisesits efficacy. To explore mechanisms of drug resistance, we treated colorectal cancer cells (HCT116 and SW620)long-term with oxaliplatin and established stable oxaliplatin-resistant lines (HCT116-OX and SW620-OX).Compared with parental cell lines, IC50s for various chemotherapeutic agents (oxaliplatin, cisplatin anddoxorubicin) were increased in oxaliplatin-resistant cell lines and this was accompanied by activation of nuclearfactor erythroid-2 p45-related factor 2 (Nrf2) and NADPH quinone oxidoreductase 1 (NQO1) . Furthermore,luteolin inhibited the Nrf2 pathway in oxaliplatin-resistant cell lines in a dose-dependent manner. Luteolin alsoinhibited Nrf2 target gene [NQO1, heme oxygenase-1 (HO-1) and GSTα1/2] expression and decreased reducedglutathione in wild type mouse small intestinal cells. There was no apparent effect in Nrf2-/- mice. Luteolincombined with other chemotherapeutics had greater anti-cancer activity in resistant cell lines (combined indexvalues below 1), indicating a synergistic effect. Therefore, adaptive activation of Nrf2 may contribute to thedevelopment of acquired drug-resistance and luteolin could restore sensitivity of oxaliplatin-resistant cell linesto chemotherapeutic drugs. Inhibition of the Nrf2 pathway may be the mechanism for this restored therapeuticresponse.