Of 50 patients with bladder cancer given 1 to 5 cycles of neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin in a pilot phase I and II study 63 per cent of 41 with pure transitional cell stage T2-4 lesions responded. While significant downstaging occurred by transurethral resection of the bladder in 70 per cent and by cytology in 60 per cent of the patients, the final T response rate by all noninvasive clinical staging procedures, including sonography and computerized tomography, revealed complete remission in 24 per cent and partial remission in 39 per cent. Of 30 patients who underwent pathological staging 33 per cent achieved stage P0 and 17 per cent stage Tis disease or P less than T. Despite extensive re-evaluation by transurethral resection of the bladder and other noninvasive staging procedures, a clinical staging error (T versus P) of 38 per cent was observed. Of the other 9 patients 4 with mixed nontransitional cell histological findings at presentation never achieved complete remission, although 3 had resolution of all transitional cell elements and 5 (10 per cent) were inevaluable. The toxicity of the regimen was generally acceptable but 6 per cent of the patients required hospitalization for neutropenic fever. While this active regimen can clinically (T) and pathologically (P) induce downstaging in a significant number of patients with primary bladder tumors, this pilot study has raised serious questions concerning the design of future nonrandomized and randomized neoadjuvant studies.