BACKGROUND: Inflammatory breast cancer (IBC) is the most aggressive manifestation of primary breast cancer. The authors compared the prognostic features of IBC and non-IBC locally advanced breast cancer (LABC) to gain insight into the biology of this disease entity. METHODS: This retrospective analysis consisted of 1071 patients, comprising 240 patients with IBC and 831 patients with non-IBC LABC who were enrolled in 10 consecutive clinical trials (5 from each disease group). All patients received similar multidisciplinary treatment. The authors measured time to disease recurrence for each individual site from the start of treatment to the date of disease recurrence or last follow-up (recurrence-free survival) and overall survival rates to the date of last follow-up or death. RESULTS: The median follow-up period was 69 months (range, 1-367 months). Pathologically complete response rates were 13.9% and 11.7% in the IBC and non-IBC LABC groups, respectively (P = .42). The 5-year estimates of cumulative incidence of recurrence were 64.8 % and 43.4% (P < .0001), respectively, for IBC and non-IBC LABC. IBC had significantly higher cumulative incidence of locoregional recurrence and distant soft-tissue and bone disease. The 5-year overall survival (OS) rate was 40.5% for the IBC group (95% CI, 34.5%-47.4%) and 63.2% for the non-IBC LABC group (95% CI, 60.0%-66.6%; P < .0001). CONCLUSIONS: IBC was associated with a worse prognosis and a distinctive pattern of early recurrence compared with LABC. These data suggested that investigating factors affecting "homing" of cancer cells may provide novel treatment strategies for IBC.