Twenty cases (fourteen males, six females, mean age 66.0) with locally advanced (T2-4 N0, M0, n = 9) or metastatic (N2-3 or M1, n = 11) urothelial cancer were treated sequentially with methotrexate (MTX) and 5-fluorouracil (5-FU), Doxorubicin (ADM), and cisplatin (CDDP) since August, 1988. Primary tumors were in the bladder in fifteen patients and in the renal pelvis or ureter in five cases. Histological findings were adenocarcinoma in one and transitional cell carcinoma in the other cases. Histological grades were grade 2 in four, grade 3 in fifteen, poorly differentiated adenocarcinoma in one. Seven patients were treated by neoadjuvant chemotherapy. Three were treated for recurrent lesions. Ten were treated for the unresectable disease. The patients received one to four cycles of this regimen (average: 2.8 cycles). Complete clinical response was observed in seven of twenty patients (35%) with measurable indicator lesions. Seven patients (35%) had a partial clinical response. Significant tumor regression was noted in fourteen of twenty patients (70%) in total, in eight of ten (80%) treated with full dose chemotherapy. The group of full dose chemotherapy showed an improved trend in survival rate as compared with the group treated by 80% and less dose chemotherapy. Toxicity was relatively mild, with anemia, leukopenia, thrombocytopenia, and no drug related death. The results suggest that the combined chemotherapy with sequential MTX and 5-FU, ADM, and CDDP is remarkably effective on advanced urothelial cancer.