PURPOSE This study sought to examine the prognostic role of p53 nuclear overexpression in muscle-invasive bladder cancer because of its correlation with progression of superficial bladder cancer. PATIENTS AND METHODS Ninety of 111 patients treated with neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) with a median follow-up duration of 5.8 years were evaluated. p53 nuclear overexpression was determined by immunohistochemistry on deparaffinized tissue sections. Patients were stratified into two groups according to the percent of tumor cells with positive nuclear reactivity. Overexpression was defined as tumors with > or = 20% cells with positive nuclear reactivity and nonoverexpression as tumors with less than 20% reactivity. RESULTS Nuclear overexpression was observed in 47 patients and nonoverexpression in 43 patients. Patients whose tumors had p53 overexpression had a significantly higher proportion of cancer deaths. A multivariate analysis that evaluated the pretreatment variables p53 nuclear overexpression, age, sex, palpable mass, prechemotherapy tumor stage, performance status, ureteral obstruction, tumor size, multifocality, and grade showed that p53 overexpression had independent significance for survival (P = .001; relative risk ratio, 3.1). The impact of p53 overexpression on survival was predominantly in T2 and T3a tumors. Long-term survival was evident in seven of 17 patients (41%) with p53 overexpression versus 20 of 26 (77%) in whom p53 was not overexpressed (P = .007). CONCLUSION p53 nuclear overexpression has independent prognostic value for survival in patients with invasive bladder cancer treated with neoadjuvant chemotherapy.