Objective: To investigate the enhancing effect of quercetin (QUE) on sensitivity of endocrine-resistant breast cancer to tamoxifen (TAM) therapy. Methods: The TAM-resistant breast cancer cell lines (MCF-7/TAM-R) were induced by high dose TAM pulse exposure, and then were transplanted into nude mice. After that, the tumor xenograft-bearing nude mice were randomly divided into 4 groups, and were administrated with vehicles (control group), QUE 50 mg/kg once every 2 days (QUE group), TAM 5 mg/kg once daily (TAM group) or QUE 50 mg/kg once every 2 days plus TAM 5 mg/kg once per day (QUE+TAM group), respectively. The general conditions of the tumor-bearing mice and the volume changes of the tumors were monitored, and the mice in each group were sacrificed at 21th day after treatment, and then the tumor weight and the expressions of ERα, HER-2, pMAPK, MAPK, pAkt and Akt in the tumor tissue were determined. Results: During treatment, the daily food intake and body weight were significantly reduced in mice of QUE+TAM group and QUE group, but showed no abnormalities in mice of control group and TAM group; the tumor growth started to decrease from the 12th day, and decreased significantly to the 21th day in QUE+TAM group (P<0.05), while the tumors grew continuously in other groups. Compared with control group, the tumor weight was significantly decreased in QUE+TAM group (P<0.05), but showed no significant difference in the other two groups (both P>0.05); the ERα protein expression was increased while HER-2, pMAPK and pAkt protein expressions were decreased markedly in the tumor tissues of QUE+TAM group and QUE group, but the expressions of all above proteins showed no obvious change in TAM control, while the expressions of unphosphorylated MAPK and Akt showed no remarkable changes in any of the groups. Conclusion: QUE can restore the sensitivity of endocrine-resistant breast cancer to TAM, which may probably be associated with its down-regulating HER-2 and downstream pMAPK and pAkt expressions, and up-regulating ERα expression; QUE has potential toxicity and adverse activities, so its safe dose range and minimum effective dose should be determined.