The expression of epidermal growth factor receptor (EGF-R), c-erbB-2 proto-oncogene, and estrogen receptor (ER) was studied immunohistochemically in a series of 97 human papillomavirus (HPV) lesions of the uterine cervix, with special emphasis on their association with the HPV type, grade of intraepithelial neoplasia (CIN), and the natural history of the disease. EGF-R expression was found in 95 of 97 (98%) specimens, mainly in basal and parabasal cells. Diffuse nuclear and cytoplasmic staining was detected in 36 of 97 (37%) samples, of which 29 were HPV positive. This staining pattern was most prominent in HPV 18-positive and in CIN lesions. Weak or moderate c-erbB-2 expression was found in 26 of 97 (27%) specimens. Estrogen receptor expression was observed in 28 of 77 (36%) samples, epithelial staining was seen in 11 of 77 (14%), and stromal staining occurred in 24 of 77 (31%) specimens. No clear-cut associations were established between the EGF-R, c-erbB-2, or ER expression and HPV type, nor in CIN or the clinical course of HPV infections. This failure for EGF-R, c-erbB-2, and ER to be associated with the specific HPV types, grade of CIN, or the clinical course of cervical HPV lesions suggests that the assessment of these factors is of limited value in explaining the development of HPV-associated CIN and in predicting the prognosis of this disease.