Glutathione (GSH) is a sulfur-containing nucleophile that protects against cisplatin-induced renal toxicity without reducing the antitumor activity of the cytotoxic agent. To document further the clinical role of GSH in improving the outcome of cisplatin-containing regimens, the feasibility of the GSH/cisplatin combination using a low-volume hydration protocol was evaluated in untreated ovarian cancer patients. Twelve patients at stage III (minimal residual disease) and 23 with localized disease at high risk for recurrence were treated with cisplatin (90 mg/m2, i.v. in 250 ml of normal saline over 30 min) and cyclophosphamide (600 mg/m2 i.v.) every 3 weeks. GSH (5 g in 200 ml of normal saline) was administered by a short-term infusion (15 min) prior to cisplatin. The hydration protocol consisted of 1 liter of fluids without diuretics. The treatment was well tolerated; no nephrotoxic or neurotoxic manifestations were observed. The renal excretion of cisplatin (23%) at 24 hours following infusion was lower than expected using a standard i.v. hydration protocol. No reduction of renal elimination of cisplatin could be detected in subsequent courses, thus suggesting a minimal degree of impairment in renal function. In the series of evaluable patients (11) with stage III disease, 9 had complete pathological response. In the series of patients with no clinically detectable disease initially, all were disease-free at treatment completion. Taken together with previous observations, these results support the view that the use of GSH is a successful approach in the attempt to optimize cisplatin treatment, providing a new modality of drug administration for out-patient treatment.