Inflammatory breast cancer (IBC) is a rare and aggressive disease requiring a multimodal treatment. We evaluated the benefit of adding docetaxel–5-fluorouracil (D-5FU) regimen after preoperative dose-intense (DI) epirubicin–cyclophosphamide (EC) and locoregional treatment in IBC patients. PEGASE 07 was a national randomized phase III open-label study involving 14 hospitals in France. Women with nonmetastatic IBC were eligible and randomly assigned to receive either four cycles of DI EC (E 150 mg/m2 and C 4000 mg/m2 every 3 weeks with repeated hematopoietic stem cell support), then mastectomy with axillary lymph node dissection, and radiotherapy (arm A) or the same treatment followed by four cycles of D-5FU (D 85 mg/m2, day 1 and 5FU 750 mg/m2/day continuous infusion, days 1–5 every 3 weeks) administered postradiotherapy (arm B). Patients with hormone receptor-positive tumors received hormonal therapy. Disease-free survival (DFS) was the primary end point. Secondary end points included tolerance, pathological complete response (pCR) rate, and overall survival (OS). Between January 2001 and May 2005, 174 patients were enrolled and treated (87 in each arm). Median follow-up was similar in both arms: 59.6 months 95% confidence interval (CI) 58.4–60.3 in arm A and 60.5 months (95% CI 58.3–61.4) in arm B. The estimated 5-year DFS rates were not different: 55% (95% CI 43.9–64.7) in arm A and 55.5% (95% CI 44.3–65.3) in arm B hazard ratio (HR) = 0.94 (0.61–1.48); P = 0.81. Identical results were observed for 5-year OS: 70.2% (95% CI 59.1–78.8) in arm A and 70% (95% CI 58.8–78.7) in arm B HR = 0.93 (0.55–1.60); P = 0.814. Following DI EC induction, in-breast and global (breast plus nodes) pCR were 28.9% and 20.1%, respectively. Estrogen receptor and pCR status were independently associated with survival. The addition of D-5FU after preoperative DI EC and standard local therapy did not improve DFS in IBC. ClinicalTrials.gov identifier: NCT02324088.