Purpose: Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer. Nuclear expression of p53 protein in breast cancer correlates with more aggressive tumors. We retrospectively analyze the expression of p53 as a prognostic marker to predict pathological complete response and survival in patients with IBC. Experimental Design: Fifty-nine patients with IBC were treated from January 1994 to April 2000. Forty-eight patients were included. Diagnostic core biopsies were taken before treatment was started. Expression of hormone receptors and p53 was determined by immunohistochemistry. All patients received an anthracycline-based regimen preoperatively; 22 patients (46%) also received paclitaxel. Forty-four patients (92%) achieved an objective clinical response and underwent mastectomies. Results: Median age at diagnosis was 48 years. Thirty patients (63%) had hormone receptor-negative tumors. Twenty-eight patients (58%) had p53-positive tumors, and 20 patients (42%) had p53-negative tumors. Nine patients (19%) achieved a pathological complete response. At a median follow-up of 77 months, 28 recurrences (58%) and 26 deaths (54%) had occurred. Patients with p53-positive tumors were younger ( P = 0.02) and tended to have lower 5-year progression-free survival rates (35% versus 55%; P = 0.3) and overall survival rates (44% versus 54%; P = 0.4). Conclusions: This retrospective analysis demonstrates that nuclear p53 protein expression may represent an adverse prognostic marker in IBC and may provide a valuable tool for selecting treatment for this aggressive disease.