BACKGROUND Overexpression of epidermal growth factor receptor (EGFR) has been reported in endometrial adenocarcinoma. METHODS A retrospective analytic study was designed to investigate its prognostic utility. Sixty-nine patients were studied with cell types that included endometrioid (n = 45), papillary serous (n = 16), and clear cell (n = 8). Patients' medical charts and survival data were reviewed. Assessment of EGFR overexpression was done at the protein level by the use of an anti-EGFR polyclonal antibody that reacts with the cytoplasmic membrane glycoprotein receptor in paraffin-embedded tissues. RESULTS EGFR was overexpressed in 34 (49%) patients in whom immunoreactivity was limited to neoplastic cells. Initial bivariate analysis revealed significant correlations between EGFR immunoreactivity and histologic grade (r = 0.44, P < 0.001), metastasis (r = 0.38, P < 0.001), cell type (r = 0.30, P < 0.01), myometrial invasion (r = 0.30, P < 0.01), and patient age (r = 0.30, P < 0.01). Multiple logistic regression analyses showed that EGFR overexpression and nonendometrioid cell types are two independent statistically significant markers for the presence of metastases. EGFR immunoreactivity can significantly predict myometrial invasion, but after controlling for the histologic grade, its ability of significantly predict invasion was lost. EGFR overexpression was shown to be a statistically significant predictor of survival, even after controlling for patient age, histologic grade, and cell type. CONCLUSIONS Expression of this oncoprotein may serve as an independent prognostic indicator and a guide to therapy in patients with endometrial cancer.