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Background Surrogate markers may be used to assess the response to neoadjuvant treatment. The association between HER2 overexpression and favorable response to specific therapy in breast cancer is controversial, and the mechanism unclear. The purpose of the study was to evaluate HER2 and topoisomerase lla (Topo Ⅱα ) as candidates for predicting the response to neoadjuvant chemotherapy in breast cancer patients.Methods Between 1999 and 2006, seventy-six breast cancer patients who had received neoadjuvant chemotherapy were studied. Regimens including either CEF (cyclophosphamide, epirubicin, 5-fluorouracil) or CMF (cyclophosphamide, methotrexate, 5-fluorouracil) were given in more than three cycles to this group of patients. Protein expression of HER2 and Topo lla were determined by immunohistochemistry. The primary endpoint was pathological and clinical response. Results Of 76 primary breast cancer samples, 27 (35.5%) showed overexpression of either HER2 (25%) or Topo Ⅱα protein (10.5%), whereas in 7 tumors (9.2%) both proteins were found to be overexpressed. Ten patients (13.2%) had a clinical complete response and 21 (27.6%) had a clinical partial response. Five women (6.6%) had a pathological complete response, 5 (6.6%) had microscopic residual disease, and 46 (60.5%) had macroscopic residual disease. HER2 and Topo lla overexpression was significantly associated with a favorable response (P <0.001 and P=0.005 respectively).Conclusion Our study suggests that HER2 and Topo Ⅱα overexpression could be predictors of the response to neoadjuvant chemothrapy in both the CEF and CMF arms.