Background: Topoisomerase II-α is a molecular target of anthracyclines; several studies have suggested that topoisomerase II-α expression is related to response to anthracycline treatment. The objective of this study was to evaluate if topoisomerase II-α overexpression predicts response to anthracycline treatment in locally advanced breast cancer patients. Material and methods: Topoisomerase II-α, HER2, estrogen receptor (ER) and progesterone receptor (PR) expression were evaluated by immunohistochemistry in formalin-fixed, paraffin-embedded breast tumors from 111 patients presenting with locally advanced breast cancer between 1995 and 2002. The prognostic value of these markers was analyzed using a multivariate proportional hazards regression model and an interaction analysis between topoisomerase II-α status and dose intensity. Results: Tumors from 40 patients (36%) showed topoisomerase II-α overexpression, 62 patients (56%) for ER, 39 (35%) for PR and 26 (23%) for HER2. There were no significant correlations between topoisomerase II-α expression and response to therapy, progression-free survival (PFS) or overall survival (OS). Anthracycline dose intensity had a significant impact on PFS and OS in patients overexpressing topoisomerase II-α (P= 0.010 and 0.027, respectively). Negative PR (P= 0.041), positive HER2 (P= 0.013) were identified as risk factors in the multivariate model. The multivariate analysis in patients topoisomerase II-α negative shown no significance (HR = 0.92, IC 95% 0.39-2.15, P= 0.839) while the multivariate analysis in topoisomerase II-α positive, dose intensity shown to be statistically significant (HR = 2.725, IC 95% 1.07-6.95, P= 0.036). Conclusions: Our data do not support a correlation between topoisomerase II-α expression in breast cancer patients and improved clinical benefit with anthracycline therapy. However, they do suggest that tumors overexpressing topoisomerase II-α may experience better clinical benefit with higher anthracycline dose intensity. © 2010 Elsevier Ltd.