The autocrine/paracrine interaction of the epidermal growth factor receptor (EGFr) and transforming growth factor alpha (TGF-alpha) has been implicated in prostate cancer cell growth and proliferation. To evaluate the role of EGFr and TGF-alpha in prostate cancer progression, we studied the immunohistochemical staining pattern of EGFr and TGF-alpha in malignant primary and hormone-independent metastatic prostate lesions. The specimens evaluated included 37 primary carcinomas (34 hormone-naive and 3 hormone-refractory tumors) and 22 metastases. For each specimen, the pattern of expression was evaluated and staining reactivities graded from 0-3, with 0 representing no staining and 3 representing homogeneous and intense staining. Primary malignant prostate epithelial cells in areas with discrete gland formation showed strong EGFr immunostaining, while stromal cells were generally nonreactive. In untreated primary tumors, TGF-alpha expression was primarily in the stroma, while epithelial cells were weakly positive in several cases. Malignant epithelial cells adjacent to neural elements that stained positive for TGF-alpha was frequently observed. A homogeneous staining pattern for EGFr was noted in 17 (89%) of 19 evaluable androgen-independent-refractory metastases, while TGF-alpha expression was found in 14 (78%) of 18 evaluable cases. Overall, 14 of 18 androgen-independent metastases coexpressed the receptor and the ligand. These results suggest that, unlike primary prostate tumors where a paracrine relationship between EGFr and TGF-alpha appears to predominate, the potential for autocrine stimulation may exist in the majority of metastatic androgen-independent tumors. Furthermore, the changing pattern of expression as the disease evolves from the localized hormone-naive to metastatic androgen-independent condition suggests that strategies aimed at blocking this growth factor pathway may be of therapeutic importance for androgen-independent disease.