C-mos is an important proto-oncogene involved in the mitogen-activating protein kinase pathway. This study was designed to explore c-mos immunoreactivity in gestational trophoblastic lesions and compare it with immunoreactivity in normal placentas as well as other gynecological lesions and germ cell tumors using antibody P-19. The immunohistochemical distribution of c-mos in 159 cases of gynecological lesions and 26 germ cell tumors using formalin-fixed, paraffin-embedded tissues was evaluated. The lesions included 45 (32 complete and 13 partial) hydatidiform moles, 17 choriocarcinomas, 5 placental site trophoblastic tumors, 18 squamous cell carcinomas and 5 adenocarcinomas of the cervix, 11 endometrial carcinomas, 9 ovarian carcinomas, 4 primary peritoneal papillary serous carcinomas, 9 low-grade endometrial stromal sarcomas, 4 epithelioid leiomyomas, 6 leiomyosarcomas, and 26 gem cell tumors (3 embryonal carcinomas, 5 yolk sac tumors, 6 immature teratomas, and 3 mature teratomas from the ovary; 9 testicular seminomas). Twenty-six normal placentas also were included for comparison. Among cases of gestational trophoblastic diseases, c-mos immunoreactivity was found in all hydatidiform moles and choriocarcinomas, but in none of the placental site trophoblastic tumors. The c-mos staining pattern was similar in trophoblastic diseases and normal placentas with strong expression in syncytiotrophoblast, moderate expression in villous intermediate trophoblast, and predominantly negative expression in implantation site intermediate trophoblast, chorionic-type intermediate trophoblast, and villous cytotrophoblast. All the nontrophoblastic tumors, including carcinomas, sarcomas, and germ cell tumors, were negative for c-mos expression. Immunohistochemical detection of c-mos is useful in differentiating choriocarcinoma from placental site trophoblastic tumor and nontrophoblastic tumors of the female genital tract that may sometimes cause problems in differential diagnosis.