We compared molecular alterations in histologically homologous ovarian and uterine carcinomas, including the prevalence of allelic loss of markers on 17q (within and distal to the familial breast-ovarian cancer gene BRCA1), mutations of codon 12 of Ki-ras and immunohistochemical expression of the p53 and c-erbB2 gene products in endometrioid and papillary serous carcinomas occurring in the uterus and ovary. A total of 86 uterine and 28 ovarian endometrioid carcinomas, as well as 8 uterine and 26 ovarian papillary serous carcinomas, were evaluated. The prevalence of p53 gene product immunoreactivity was similar in papillary serous carcinomas occurring in the uterus (6 of 8, 75%) and ovary (16 of 26, 62%). Allelic loss on 17q also was seen in similarly high proportions of uterine (3 of 7, 43%) and ovarian (16 of 25, 64%) papillary serous carcinomas. In contrast, expression of the p53 gene product was seen in significantly more endometrioid tumors of the ovary (14 of 28, 50%) than in those occurring in the uterus (4 of 86, 5%) (p < 0.0001). Allelic loss on 17q also was present in significantly more ovarian (19 or 27, 70% than in uterine (2 of 72, 3%) endometrioid carcinomas (p < 0.0001). Immunohistochemical expression of c-erbB2 and mutations of codon 12 of Ki-ras were present in a minority of carcinomas. Endometrioid tumors of the ovary and endometrium, although histologically similar, may arise from different genetic events, whereas uterine papillary serous carcinoma shares with its ovarian counterpart several molecular alterations that may account for its aggressive clinical behavior.