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Objective: To evaluate the effectiveness of cyclophosphamide and methylprednisolone pulse therapy in the prevention of pulmonary fibrosis due to paraquat poisoning in rats., Methods: This study was carried out in Sina Hospital, Tabriz, Iran, between February and August 2009. Acute poisoning in rats was induced by intraperitoneal injection of Paraquat (15 mg/kg). We planned 2 separate treatment groups (10 rats each), pulse therapy with methylprednisolone (26.5 mg/kg) and cyclophosphamide (15 mg/kg) intraperitoneally for 3 days (PQ+P) and treatment with conventional anti-oxidant drugs including vitamin A, vitamin E, and N-acetylcysteine (PQ+Vit). Prevention of pulmonary fibrosis was evaluated on the fifteenth day. A semi-quantitative determination of lung fibrosis was carried out (Ashcroft staging criteria) on the lung sections and results compared with the paraquat control group (PQ)., Results: The mean score of fibrosis in the PQ was 4.60+/-1.20, in PQ+P was 2.93+/-0.72, and for PQ+Vit groups was 4.25+/-1.08. The score of fibrosis in the PQ+P was significantly lower than the PQ group (p=0.011), while there was no significant difference in the average score of lung fibrosis between the PQ and PQ+Vit groups., Conclusion: Pulse therapy with cyclophosphamide and methylprednisolone significantly prevented pulmonary fibrosis. Therefore, we recommend it along with conventional therapies in the treatment of acute paraquat poisoning.