Background: Clinicopathological implications of SPAG5 were investigated in BC. Methods: SPAG5 copy number changes and gene expression were investigated in 1980 cases of BC (METABRIC cohort) and validated in multicentre databases (n = 3500). SPAG5 protein expression was evaluated in three primary BC cohorts (n = 2250) with 20-year-median follow-up. The response to chemotherapy (CT) was investigated in two cohorts in whom pathological complete response (pCR) was the primary endpoint: a) Multicentre phase II trial (NCT00455533; n = 295) received doxorubicin/cyclophosphamide followed by 1:1 randomisation to ixabepilone or paclitaxel and b) 250 BC treated with neoadjuvant-anthracycline (AC). BC cell lines with high (+) and low (-) SPAG5 expressions were tested for CT sensitivity. Results: 10-20% of BC showed gain/amplification of SPAG5 locus at Ch17q11.2. SPAG5 gain/amplification and mRNA+ were significantly associated with: TP53 mutation; PAM50 Her2; PAM50 Basal; PAM50 LumB and integrative molecular clusters 1, 5, 9 and 10 (p < 0.0001). SPAG5 gain/amplification, mRNA+ and protein+ were associated with poor survival and were independent prognostic factor (p < 0.0001). In the clinical trial, SPAG5 mRNA+ was associated with higher pCR (OR = 2.3, 95% CI = 1.2-4.2, p = 0.008), especially among ER- BC (OR = 2.8, 95% CI = 1.3-5.9, p = 0.007). Patients with SPAG5-mRNA+ in the ixapeblone arm achieved higher pCR in all patients (OR = 3.0, 95% CI = 1.3-7.1, p = 0.01) and ER- cases (OR = 4.2, 95% CI = 1.3-13.0, p = 0.01). In the paclitaxel arm there was no statistical association between pCR and SPAG5 mRNA level. SPAG5-protien+ was shown to be an independent predictor for pCR (OR; 2.4; 95% CI = 1.6-3.9, p < 0.001). In in vitro cell line models, SPAG5+ expression was linked to cell response to CT drugs, irrespective of ER and TP53 status. For instance, T47D and BT549 cell lines with SPAG5+ expression were sensitive to Doxorubicin and knocking-down of SPAG5 made cells resistant to CT agents. Conclusions: SPAG5 is a novel amplified gene on ch17.q11 and is an independent prognostic factor. SPAG5 could help in the selection of patients who will benefit from AC-CT. and its interaction with TP53 need to be explored.