Tamoxifen, an important endocrine therapeutic agent, is widely used for the treatment of estrogen receptor positive (ER+) breast cancer. However, de novo or acquired resistance prevents patients from benefitting from endocrine approaches and necessitates alternative treatments. In this study, we report that small heat protein beta-8 (HSPB8) may serve as an important molecule in tamoxifen resistance. HSPB8 expression is enhanced in MCF-7 cells resistant to tamoxifen (MCF-7/R) compared to parent cells. Moreover, high expression of HSPB8 associates with poor prognosis in ER+ breast cancer patients but not in patients without classification. Stimulating ER signaling by heterogeneous expression of ERa or 17β-estradiol promotes HSPB8 expression and reduces the cell population in G1 phase. In contrast, blockage of ER signaling by tamoxifen down-regulates the expression of HSPB8. In addition, knocking down HSPB8 by specific siRNAs induces significant cell cycle arrest at G1 phase. AZD8055 was found to be more potent against the proliferation of MCF-7/R cells than that of parent cells, which was associated with down-regulation of HSPB8. We found that the anti-proliferative activity of AZD8055 was positively correlated with the HSPB8 expression level in ER+ breast cancer cells. Thus, AZD8055 was able to overcome tamoxifen resistance in breast cancer cells, and the expression of HSPB8 may predict the efficacy of AZD8055 in ER+ breast cancer. This hypothesis deserves further investigation.