The degree of expression of p53 and proliferating cell nuclear antigen (PCNA) was measured in archival samples from 221 patients managed surgically for endometrial carcinoma between 1979 and 1983. With use of primary antibodies to the p53 protein (DO7) and PCNA (PC10), immunoperoxidase nuclear staining of paraffin-embedded tissue was performed. The computerized CAS200 Image Analysis System was used to determine the percentage of nuclear area stained. There was no evidence to conclude that progression-free survival differed with respect to PCNA expression. In contrast, intense p53 expression (66% or more nuclear area stained) was significantly associated with compromised progression-free survival both in the analysis of all stages (P < 0.001) and in the subset of patients with stage I disease (P < 0.001). Intense expression of p53 was significantly associated with other prognostic indicators, including stage, grade, depth of myometrial invasion, histologic subtype, cytologic findings, DNA ploidy, and HER-2/neu expression. Multivariate analysis identified four independent prognostic factors for progression-free survival in endometrial carcinoma: intense p53 expression, histologic subtype, DNA ploidy status, and HER-2/neu expression. When none of these four independent factors are present, the 4-year progression-free survival is 96%. In contrast, it is 63% when one or more of these factors are present (P < 0.001) and 40% when two or more factors are present (P < 0.001).