Purpose: The loss of p53 function is a recognized adverse prognostic factor in invasive breast cancer. Several studies have shown a relationship between the nuclear accumulation of p53 protein (a surrogate marker of 953 inactivation) and poor disease-free and overall survival, In general, however, these studies did not report the prognostic value of 953 for local failure, which we have therefore assessed retrospectively here. Materials and Methods: Accumulation of 953 protein was evaluated by immunohistochemistry in 1,530 mastectomy-treated breast cancer patients (259 radiation therapy [RT]- and 1,271 mastectomy only [No RT]-treated patients), Statistical comparisons were made between 953 protein accumulation, estrogen/ progesterone receptors, nodal status, tumor size, and local failure rate (LFR), Local failure was defined as tumor recurrence involving the chest wall and/or the ipsilateral supraclavicular/axillary lymph nodes, The median follow-up period was 62 months, Results: In the No RT group, the LFR was 9.1% and 16.5% in p53-negative and p53-positive patients, respectively (P < .001), Multivariate analysis revealed that 953 protein accumulation was significantly associated with an increased risk of local relapse (relative risk [RR], 1.7; 95% confidence interval [CI], 1.2 to 2.4), Nodal status and tumor size were also significant factors, In the RT group, the LFR was 9.3% and 21.5% in p53-negative and p53-positive patients, respectively (P = .009). Multivariate analysis revealed that 953 pratein accumulation was significantly associated with an increased risk of local relapse (RR, 2.5; 95% Cl, 1.1 to 5.7), as was nodal status, Conclusion: Nuclear accumulation of 953 protein is independently associated with a significantly increased local failure rate in breast cancer patients treated with mastectomy, with or without radiation. (C) 2000 by American Society of Clinical Oncology.