Abstract Background Inflammatory breast cancer (IBC) is a unique clinicopathologic entity that is characterized by rapid progression and aggressive behavior from the onset. The clinical presentation consists of erythema, rapid enlargement of the breast, skin ridging, and a characteristic peau d'orange appearance of the skin secondary to dermal lymphatic tumor involvement. Because of its uncommon presentation leading to frequent misdiagnosis, most reports are from small single institution series which describe a predictable pattern of recurrence in spite of appropriate multidisciplinary treatments. We sought to confirm these observations using the large multi-institutional National Comprehensive Cancer Network (NCCN) outcomes database. Methods: Patients (pts) with newly diagnosed IBC treated between 1999 and 2009 at 12 participating NCCN institutions were identified. The clinical diagnoses of IBC was based on the AJCC definition and staged as clinical T4d, N0-3, M0-1. The baseline pathological characteristics included histological type, estrogen receptor (ER), progesterone-receptor (PR), and HER-2/neu status. Pts were classified as receiving multimodality therapy if they received two of the following three treatments: surgery (lumpectomy or mastectomy), perioperative (neoadjuvant or adjuvant) systemic therapy, or perioperative radiation therapy. Results: We identified a cohort of 673 pts with newly diagnosed IBC with a median follow-up of 28.9 months. Of which 195 (29%) had metastatic disease at presentation. The median age at presentation was 52.6 years. Caucasians were 79.4% of the cohort, African American 9.7%, and 11.0% other ethnic groups. Invasive ductal type comprised 84% of histologies. Biomarker assessment revealed ER+ (44.7%), PR+ (34.3%), and Her2/neu+ (33.4%). LVI was documented in 53.3%. Of stage III patients, 75.7% pts received perioperative radiation, 82% received perioperative systemic therapy and 70.7% underwent surgery. All three modalities were received by 64.4% of women. Of the stage III pts, 203 recurred. The most frequent sites of recurrence for were CNS (20.2%), bone (17.2%), chest wall (13.8%), lung (12.3%), liver (11.3%), distant (7.4%) and regional lymph nodes (6.9%). With a median of 30 and 20 months of follow-up for stage III & IV respectively, the median survival was 66 months (95% CI 54–107) for stage III pts and 26 months (95% CI: 22–33) for stage IV Among the 82% of stage III pts who received multimodality therapy, the 5 year and 10 year OS of 62% and 47%. Discussion: This is a large retrospective multiinstitutional study that confirms the aggressive clinical features, recurrence patterns and adverse prognosis of IBC described in previous single institution series. Even with aggressive multimodal therapy, the long term survival of IBC shorter is than non-IBC. Future investigations are needed to address the aggressive biology of IBC to improve diagnosis and therapy. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-20-02.