Background: We recently have identified SPAG5 as a novel oncogene that was common in PAM50 Luminal B. Herein, we test the prognostic and predictive significance of SPAG5 gene, transcript and protein expression in ER+ BC. Methods: The correlation between SPAG5 gene copy number aberrations and its transcript with BC specific survival (BCSS) were determined in the ER+ subgroup of the METABRIC (Molecular Taxonomy of BC International Consortium; n = 1498), the Cancer Genome Atlas BC project (TCGA BRCA; n = 709) and in publically available ER+ BC genomic datasets (n = 3044). The relationship between SPAG5 mRNA and protein expression with relapse free survival (RFS) was studied in untreated lymph node negative ER+ BC (n = 606 and 588; respectively) and in ER+ patients treated with 5 years of adjuvant tamoxifen (n = 876 and 429; respectively). The relationship between the pathological complete response (pCR) after anthracycline neoadjuvant chemotherapy (AC Neo ACT) with SPAG5mRNA [(MD Anderson cohort (n = 297) and NCT00455533 phase II trial (n = 101)] and protein expression [Nottingham cohort; (n = 200)] was also tested. The median values of SPAG5 mRNA and protein expression were used as cut-offs. Results:SPAG5 gain/amplification was found in 165/1498 (11%; METABRIC) and 137/709 (19.3%; TCGA-BRCA) of ER+ BCs, and was more common in ER+HER2+ compared to ER+HER2- (31.3% vs., 13.6%) and was associated with shorter BCSS (HR (CI 95%): 1.55 (1.18-2.04), p = 0.00021). In untreated ER+LN- and tamoxifen treated ER+Luminal A BC, mRNA SPAG5+ was associated with shorter RFS [(HR (CI 95%): 1.25 (1.11-1.42), p = 0.0003) and [(HR (CI 95%): 1.66 (1.16-2.39), p = 0.0053); respectively]. In tamoxifen treated ER+Luminal B BC SPAG5 mRNA (+) and (-) had similar RFS (HR (CI 95%): 1.15 (0.76-1.74), p = 0.50). Multivariable logistic regression model showed SPAG5mRNA+ to predict pCR in ER+ BC treated with AC Neo ACT [MD Anderson cohort (OR (95%CI): 2·18 (1·08-4·38); p = 0·029 and Phase II trial (OR (CI 95%): 3·83 (1·01-14·55); p = 0·049)]. Conclusions: SPAG5 is a prognostic biomarker that predicts response to AC-Neo-ACT in ER+BC which can help to optimize systemic treatment in luminal B-BC.