BACKGROUND: Neuroendocrine carcinoma (NEC) of the breast, a pathologic entity newly defined in the 2003 World Health Organization classification of tumors, is a rare type of tumor that is not well recognized or studied. The purpose of this first case-controlled study is to reveal the clinicopathologic features, therapeutic response, and outcomes of patients with NEC of the breast. METHODS: Seventy-four patients with NEC of the breast who were treated at The University of Texas M. D. Anderson Cancer Center were analyzed; 68 of them had complete clinical follow-up. Two cohorts of invasive mammary carcinoma cases were selected to pair with NEC to reveal demographic, pathologic, and clinical features at presentation, along with therapeutic response to treatment and patient outcomes. RESULTS: NEC was more likely to be estrogen receptor/progesterone receptor positive and human epidermal growth factor receptor 2 negative. Despite similar age and disease stages at presentation, NEC showed a more aggressive course than invasive ductal carcinoma, with a higher propensity for local and distant recurrence and poorer overall survival. High nuclear grade, large tumor size, and regional lymph node metastasis were significant negative prognostic factors for distant recurrence-free survival; high nuclear grade and regional lymph node metastasis were also significant negative prognostic factors for overall survival. Although endocrine therapy and radiation therapy showed a trend toward improved survival, the small number of cases in this study limited the statistical power to reveal therapeutic benefits in NEC of the breast. CONCLUSIONS: NEC is a distinct type of aggressive mammary carcinoma. Novel therapeutic approaches should be explored for this uniquely different clinical entity. © 2010 American Cancer Society.