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Objective: To observe the damage of mixed reflux to the rat esophageal mucosa, and investigate the preventive effects of cisapride, nabumetone and hydrotalcite on the damaged esophageal mucosa. Methods: Three hundred sixty-eight Sprague-Dawley rats were treated as esophagoduodenostomy and divided into four groups in random. Group Y: operation + saline as positive controls; Group P: operation + cisapride; Group R: operation + nabumetone; Group D: operation + hydrotalcite. Different drugs were perfused in the 1 st week after operation. The lesions of esophageal mucosa were observed in the 5th, 9th, 13th, 17th, 22nd, 28th, 35th and 40th week respectively, and evaluated the preventive effects of these drugs. Results: The lesions of esophageal mucosa in group Y were more severe than other three groups in different time (P ＜ 0.05), and the incidence of Barretts esophagus(BE), severe atypical hyperplasia and esophageal adenocarcinoma (EAC) in group Y were higher than others. After 22 weeks, the lesions in group P were more severe than group R and D, and there were obvious differences in different time ( P ＜ 0.05); but the incidence of BE, severe atypical hyperplasia and EAC in group P had no significant difference with group R and group D( P ＞ 0.05). Conclusion: BE, severe atypical hyperplasia and EAC could occur because of severe reflux esophagitis for a long term. Cisapride, nabumetone and hydrotalcite could reduce mucosa injury in reflux esophagitis and resist the development of BE, severe atypical hyperplasia and EAC.In addition, the curative effects of nabumetone and hydrotalcite were better than cisapride.