We analyzed the role of endocrine responsiveness and HER2/neu overexpression in inflammatory breast cancer treated with multimodality preoperative therapy. Thirty-eight patients (estrogen receptor [ER] and/or progesterone receptor [PgR] >or=10% of the cells 21, premenopausal 14, Ki-67 expression >or=20% of the cells 30, HER2/neu overexpressed 11) were treated with six courses of epirubicin, cisplatin and fluorouracil (FU) as continuous infusion, perioperative FU as continuous infusion, mastectomy and loco-regional radiotherapy. In endocrine-responsive patients, endocrine treatment (letrozole, either alone or if premenopausal with triptorelin) was given preoperatively and as adjuvant treatment. There were 32 objective responders (84.2%; 95% CI 70.0-94.6%), three of whom had pathologic complete remission. At the multivariate analysis disease-free survival was significantly worse in patients with ER and PgR absent tumors compared with the positive expression cohort (hazards ratio [HR]: 5.91; 95% CI 1.69-20.7; p = 0.005), in particular if HER2/neu overexpression was detected (HR: 16.5; 95% CI 4.24-64.5; p < 0.0001). New multimodality and targeted strategies should be explored in endocrine nonresponsive breast cancer.