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Background Human epidermal growth factor receptor-2 (HER2) is overexpressed in 20–25% of breast cancers. Complete eradication of disease following neoadjuvant therapies and chemotherapy has been referred to as pathological complete response (pCR). Aims To determine clinicopathological predictors of pCR to neoadjuvant therapies and to evaluate pCR as a surrogate to enhanced survival. Methods Consecutive female patients with HER2 positive (HER+) breast cancer managed surgically in a single institution between 2005 and 2015 were included. Descriptive statistics and binary logistic regression were used to determine predictors of pCR. Appraisal of pCR as a predictor of survival was performed using Kaplan-Meier curves and Cox regression analysis. Results 451 patients were included with a mean age of 56.6 ± 13.4 years (range 23–95). Disease-free (DFS) and overall survival (OS) was 82.3% (371/451) and 82.6% (376/451) respectively with a median follow-up of 108.0 months (range 3–184.0). 118 were treated in the neoadjuvant setting (26.2%): tumour size, Highlights • Clinicopathological data predict patients who achieve pCR in HER2+ breast cancer. • pCR is a sensitive biomarker of survival in HER2 positive breast cancer. • Patients achieving pCR have reduced risk of breast cancer recurrence and mortality. • pCR can aid patient prognostication in the era of personalised medicine.