BACKGROUND: Trastuzumab (TZ) therapy requires careful monitoring of left ventricular (LV) ejection fraction (LVEF) because it can be potentially cardiotoxic. However, LVEF is an imperfect parameter and there is a need to find other variables to predict cardiac dysfunction early. Left atrium (LA) enlargement has proven to be a powerful predictor of adverse outcomes in several disease entities. HYPOTHESIS: Baseline LA volume enlargement might predict TZ‐related LV dysfunction. METHODS: HER2‐positive breast cancer patients receiving TZ and undergoing transthoracic echocardiography at baseline and at follow‐up every 3 months were retrospectively recruited. One‐hundred sixty‐two patients formed the study population. RESULTS: Baseline LAVI was dilated in 14 patients (8.6%). Mean follow‐up was 14 ± 4 months. Cardiotoxicity occurred in 24 patients (14.8%). LAVI was an independent predictor of TZ‐induced LV dysfunction in a clinical model, after adjustment for age and hypertension (odds ratio per 5‐mL/m(2) LAVI increase: 1.34, 95% confidence interval: 1.03‐1.82, P = 0.03); and in a hemodynamic model, including ventricular sizes and systolic blood pressure level (odds ratio per 5‐mL/m(2) LAVI increase: 1.34, 95% confidence interval: 1.01‐1.81, P = 0.04). The predicted probability of developing cardiotoxicity increased progressively, in parallel with LAVI values. CONCLUSIONS: Baseline LA dilatation emerges as a condition associated with the development of cardiotoxicity in HER2‐positive breast cancer patients treated with TZ.