We examined the presence of human chorionic gonadotropin (HCG) in 16 low-grade and 47 high-grade urothelial neoplasms, including two cases with trophoblastic-like differentiation. In HCG-positive tumors, the presence of human placental lactogen (HPL) and pregnancy-specific beta-1-glycoprotein (SP-1) also was assessed. HCG immunoreactive cells were found in nine of the 47 high-grade tumors (19%), whereas none of the low-grade tumors were positive for HCG. This hormone was predominantly detected in the most undifferentiated and pleomorphic areas; however, HCG-positive cells also were found in areas of carcinoma in situ and well-differentiated transitional cell carcinoma in two cases. The serum HCG level was increased in two of the four cases studied. HPL and SP-1 immunoreactive cells were observed in seven and five cases, respectively, and it was found that tumors positive for SP-1 also were positive for HPL. Five tumors, including the two with trophoblastic differentiation, contained the three placental proteins. The HPL and SP-1 immunostained cells were usually found in the same areas of the tumor that were positive for HCG, but there was always a lower number of HPL and SP-1 immunoreactive cells than HCG immunoreactive cells. In one case, HPL and SP-1 could be found in areas of well-differentiated transitional cell carcinoma. These findings suggest that the morphologic and functional trophoblastic differentiation in urothelial carcinomas is a progressive phenomenon evolving from transitional cell carcinomas.