From September 1984 to December 1988, 28 consecutive patients with metastatic urothelial cancer entered a randomized study to compare 4 courses of modified methotrexate, vinblastine, adriamycin and cisplatin (M-VAC) to 4 courses of methotrexate followed by folinic acid rescue and cisplatin (MP). Non-responders or relapsing patients were to be crossed to the other therapy. Hematological toxicity was more frequent (85%), but less severe, in patients treated with M-VAC than in patients treated with MP (21%, with 1 septic death). Complete plus partial remissions were achieved in 10 (71.4%) of 14 patients treated with M-VAC and in 6 (50%) of the 12 evaluable patients treated with MP. The 20% difference lay only on complete remissions, which were 8.3% in the MP versus 28.5% in the M-VAC group. At cross-over, however, only 1 of 5 patients resistant to MP responded to M-VAC, while 3 of 5 patients resistant to M-VAC responded to MP. It seems that M-VAC should be considered as the first-line therapy of choice in metastatic urothelial cancer, while MP, or high-dose methotrexate, could be considered for salvage.