Objective: To investigate the mechanism of progranulin (PGRN) in the development of tamoxifen resistance of human breast cancer cells. Methods: The breast cancer MCF-7 and T47D cells as well as tamoxifen-resistant MCF-7R and T47DR cells were treated by 4-hydroxytamoxifen (OHT). The 50% inhibitory concentration (IC50) of OHT was detected by CCK-8. The expressions of C-myc, Cyclin D1 and Bcl-2 were determined by Western blotting. The cell proliferation was detected by CCK-8, the apoptosis was detected by FCM. The expression levels of PGRN mRNA and protein were detected by real-time fluorescent quantitative PCR and Western blotting, respectively. The expression of PGRN in MCF-7R and T47DR cells was interfered by transfection of PGRN-siRNA. Then the changes of PGRN, C-myc, Cyclin D1 and Bcl-2 expressions were detected by Western blotting. Furthermore, the PGRN-interfered MCF-7R and T47DR cells were stimulated by OHT, then the apoptosis was tested by FCM again. Results: The IC50 of OHT in tamoxifen-induced MCF-7R or T47DR cells was higher than that of MCF-7 or T47D cells (both P < 0.001). As compared with MCF-7 or T47D cells, the proliferation of MCF-7R or T47DR cells was enhanced (both P < 0.01), the apoptotic rate was decreased (both P < 0.01), the expressions of proliferation-related proteins C-myc and Cyclin D1 as well as apoptosis-related protein Bcl-2 were significantly increased (all P < 0.01), and the mRNA and protein levels of PGRN were significantly increased in MCF-7R and T47DR cells (both P < 0.05). After the transfection of PGRN-siRNA into MCF-7R and T47DR cells, the protein levels of PGRN, C-myc, Cyclin D1 and Bcl-2 were significantly decreased (all P < 0.01). After stimulation with OHT, the apoptosis rate of PGRN-downregulated MCF-7R and T47DR cells was increased (both P < 0.01). Conclusion: PGRN is overexpressed in human breast cancer MCF-7R and T47DR cells with tamoxifen-resistance. Interference of PGRN gene expression can enhance the sensibility of breast cancer cells to tamoxifen.