Background: Nephrotoxicity is one of the major side-effects of cisplatin that has been seen in about 20% of treated patients. The aim of this study was to assess the effectiveness of a forced hydration protocol comprised of isotonic saline, potassium chloride (KCl) and magnesium sulfate (MgSO4) on prevention of cisplatin nephrotoxicity. Methods: This cross sectional prospective study was performed on cancer patients treated in Shafa Hospital, Ahvaz, Iran from November 2009 to March 2010. The patients were under at least 50 mg/m 2 cisplatin. All patients received 1000 mL isotonic saline plus 20 mEq of KCl and 2 g of MgSO 4 during 2-3 hours before, and 500 mL of the same solution over the two hours after administration of cisplatin. The prescribed dose of the solution was to the extent facilitating a urine flow of at least 100 mL/h for two hours prior to chemotherapy and 2 hours post-chemotherapy. Cisplatin nephrotoxicity was defined as an increase in the SCr equal or over 0.5 mg/dL during the 5 day follow-up post-chemotherapy. Results: A total of 76 patients (48 men and 28 women with mean (SD) age of 51.0 (17.6) years) were studied. Mean cumulative cisplatin dose was 86.7 (43.1) mg/m 2 . Hypokalemia and hypomagnesemia were not observed in any patient. Cisplatin nephrotoxicity (increase of creatinine) was developed in 5 patients (6.6%). The mean dose of cisplatin in patients with andwithout nephrotoxicity was 83 and 86.97 mg respectively which showed no significant difference between them (P = 0.8). Conclusion: The new protocol was able to decrease the rate of cisplatin nephrotoxicity from about 20% to 6.6%. Further case control studies with larger sample sizes are recommended to evaluate the effectiveness of this protocol.