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Background A meta-analysis of the effects of HER2 status, specifically within the first 2–3 years of adjuvant endocrine therapy, has the potential to inform patient selection for upfront aromatase inhibitor (AI) therapy or switching strategy tamoxifen followed by AI. The pre-existing standardisation of methodology for HER2 (immunohistochemistry/fluorescence in situ hybridization) facilitates analysis of existing data for this key marker. Methods Following a prospectively designed statistical analysis plan, patient data from 3 phase III trials Arimidex, Tamoxifen, Alone or in Combination Trial (ATAC), Breast International Group (BIG) 1-98 and Tamoxifen Exemestane Adjuvant Multicentre Trial (TEAM)] comparing an AI to tamoxifen during the first 2–3 years of adjuvant endocrine treatment were collected and a treatment-by-marker analysis of distant recurrence-free interval-censored at 2–3 years treatment – for HER2 status × AI versus tamoxifen treatment was performed to address the clinical question relating to efficacy of ‘upfront’ versus ‘switch’ strategies for AIs. Results A prospectively planned, patient-level data meta-analysis across 3 trials demonstrated a significant treatment (AI versus tamoxifen) by marker (HER2) interaction in a multivariate analysis; (interaction hazard ratio [HR] = 1.61, 95% CI 1.01–2.57; p < 0.05). Heterogeneity between trials did not reach statistical significance. The HER2 negative (HER2−ve) group gained greater benefit from AI versus tamoxifen (HR = 0.70, 95% CI 0.56–0.87) than the HER2-positive (HER2+ve) group (HR = 1.13, 95% CI 0.75–1.71). However, the small number of HER2+ve cases (n = 1092 across the 3 trials) and distant recurrences (n = 111) may explain heterogeneity between trials. Conclusions A patient-level data meta-analysis demonstrated a significant interaction between HER2 status and treatment with AI versus tamoxifen in the first 2–3 years of adjuvant endocrine therapy. Patients with HER2−ve cancers experienced improved outcomes (distant relapse) when treated with upfront AI rather than tamoxifen, whilst patients with HER2+ve cancers fared no better or slightly worse in the first 2–3 years. However, the small number of HER2+ve cancers/events may explain a large degree of heterogeneity in the HER2+ve groups across all 3 trials. Other causes, perhaps related to subtle differences between AIs, cannot be excluded and warrant further exploration. [ABSTRACT FROM AUTHOR]