Background: Cylophosphamide is used alone or in combination with other drugs for treatment of neoplastic diseases. Hemorrhagic cystitis is a major potential toxicity and dose limiting side effect of cyclophosphamide. The aim of this study was to evaluate the effects of lycopene compared with some antioxidants for the prevention of cyclophosphamide induced hemorrhagic cystitis in rats. Methods: In this study, male Sparague-Dawley rats divided into 17 groups of six animals. Group 1 received saline (10 ml/kg, i.p) as normal control, group 2 received cyclophosphamide (200 mg/kg, i.p) as a single dose, groups 3-10 received Mesna (40 mg/kg, i.p), N-acetylcysteine (100 mg/kg i.p), dithiotheritol (50 mg/kg, i.p), L-carnitine (200 and 400 mg/kg, i.p), grape seed extract (500 mg/kg i.p) and lycopene (0.1 and 0.5 mg/kg, i.p) alone. Groups 11-17 received Mesna (40 mg/kg, i.p), N-acetylcysteine (100 mg/kg, i.p), dithiotheritol (50 mg/kg, i.p), L-carnitine (400 mg/kg, i.p), grape seed extract (500 mg/kg, i.p) and lycopene (0.1 and 0.5 mg/kg, i.p), 5 minutes before, and 2 and 6 hours after administration of 200 mg/kg cyclophosphamide. Pathological and biochemical analysis was evaluated 24 hours after cyclophosphamide administration. Results: Mesna and N-acetylcysteine resulted in some but not full protection against cyclophosphamide toxicity compared to the controls. Lycopene (0.1 and 0.5 mg/kg) was efficient in protecting the bladder from cyclophosphamide induced hemorrhagic cystitis. However, dithiotheritol, L- carnitine and grape seed extract did not prevent hemorrhagic cystitis. Conclusion: Our results suggest that pre and co- treatment of lycopene (0.1 and 0.5 mg/kg) with cyclophosphamide may have therapeutic potential to inhibit the hemorrhagic cystitis by cyclophosphamide.