Using differential polymerase chain reaction (DPCR), dot blot hybridization, and an immunohistochemical technique, we determined the amplification and expression of the c-erbB-2 oncogene in 25 normal, 31 hyperplastic, and 72 malignant samples of the endometrium in 128 patients. Using DPCR, we found amplified c-erbB-2 (two to 12 copies) in two of 25 (8%) normal, 15 of 31 (48%) hyperplastic, and 45 of 72 (63%) malignant samples. These results were closely correlated with those from dot blot (r = 0.78). When comparing the results of DPCR with those of the immunohistochemical method, we noted that the negative findings coincided with one another, i.e., nonamplification was associated with the absence of immunoreactivity. Further analysis showed that amplified c-erbB-2 was found significantly more in complex and atypical hyperplasias versus simple hyperplasias. This indicates that c-erbB-2 may play a potential role in the early development of some endometrial carcinomas. Although no correlation was seen between c-erbB-2 amplification and overall survival in our patients, high-level c-erbB-2 amplification (at least five copies) was significantly associated with the histological grade of endometrial carcinoma and vascular or lymphatic invasion. It is possible that high-level c-erbB-2 amplification identifies a subset of aggressive endometrial carcinoma that involves vascular or lymphatic invasiveness and poor cell differentiation.