High-dose ifosfamide (one or two courses of 6 g/m2) with or without mesna was administered to 13 patients with advanced non-small cell lung cancer. The protective effect of 2-mercapto-ethane sulfonate (mesna) against the urotoxic side effects induced by ifosfamide was examined by a randomized crossover trial. A significant reduction in the incidence of hematuria was observed in the patients receiving mesna. Macroscopic hematuria was observed in only one patient who received treatment with mesna versus seven patients treated with ifosfamide alone. Other symptoms, such as frequency and dysuria, tended to be diminished in the patients receiving mesna, although the difference was not statistically significant. Our results suggest that mesna is effective in preventing or diminishing ifosfamide-induced hemorrhagic cystitis. Concomitant use of mesna should allow the administration of a high dose of ifosfamide although more extensive studies are needed to define the optimal dose and schedule of administration of mesna to prevent or attenuate the hemorrhagic cystitis.