The prognostic significance of p53 expression in 316 archival epithelial ovarian cancers was assessed using a static, computer-aided image analysis system (CAS 200). Using a 10% cut-off point, 26% of primary tumors and 35% of their metastases were positive for p53 protein. p53 positivity closely correlated with tumor grade (p < 0.001), stage (p < 0.001), residual tumor (p < 0.001), serous histologic type (p = 0.005), and tumor recurrence (p = 0.007). The overall 5-year survival was 37%. In univariate survival analysis, high grade, advanced stage, older age at diagnosis, and residual tumor > 2 cm were significant predictors of poor overall survival. In both the overall (p < 0.001) and recurrence-free (p < 0.001) survival, p53 immunopositivity predicted poor prognosis. p53 expression was a significant prognostic factor of multivariate recurrence-free survival (RR 1.93, p = 0.03), but not of overall multivariate survival. In addition, p53 positivity was a marker of poor overall survival in patients with well or moderately differentiated tumors, early stage tumors, or residual tumor. Quantitation of p53 immunoexpression by CAS may offer an objective means to identify patients who need more aggressive adjuvant therapy or new treatment strategies.