In order to evaluate the outcome of patients with breast cancer according to response after primary therapy and according to clinical and biologic baseline features, we identified patients who were treated with preoperative therapy and who underwent surgery at the European Institute of Oncology (IEO), Milan, Italy, between 1995 and 2006. The outcome of patients who achieved pathological complete remission (pCR) and patients with residual disease (RD) at final surgery was analyzed. Of the 687 patients treated with preoperative therapy, we identified 82 patients who achieved pCR (12%) and 605 patients with RD (88%). A statistically significant difference in disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) was observed for patients with pCR compared with those who had RD (5 year DFS 73% vs. 59% P = 0.029; 5 year DDFS 81% vs. 72% P = 0.085; 5 year OS 88% vs. 77% P = 0.033). At the multivariate analysis, for patients achieving pCR, large tumor size (> 5 cm) correlated with worse DFS (HR 3.18; 95% CI 1.34-7.51); clinical nodal involvement was associated with poorer DFS and DDFS (HR 6.94; 95% CI 1.62-29.73 and HR 9.87 95% CI 1.29-75.53, respectively). pCR after preoperative systemic therapy correlated with significant improved outcome. A substantial rate of relapse was observed for patients with large tumors and with clinical nodal involvement at baseline. Further improvement in adjuvant treatment might be warranted.