Objective:To investigate the protective effects and possible mechanisms of new Wenshen Shengjing Decoction(new WSSJD) on cyclosporine-induced oxidative stress to epididymal tissue and sperm in mice. Methods Eight-week-old male Kunming mice were randomly assigned into normal control group, solvent group, model group, western medicine group and Chinese medicine group, 15 mice in each group. Mice in normal control group received intraperitoneally normal saline, and mice in western medicine group, Chinese medicine group and model group were injected intraperitoneally with cyclosporine(15 μg·g-1·d-1) for 30 days; meanwhile, mice in western medicine group and Chinese medicine group were respectively gavaged with clomifene citrate and new WSSJD for 30 days consecutively. The body weight and epididymal weight were recorded; the contents of malondialdehyde(MDA) and glutathione(GSH) and activity of glutathione peroxidase(GSH-Px) in epididymal tissue were detected; the ROS level, apoptosis and death of sperms in mice epididymis were examined by flow cytometry assay.  Results: Compared with the normal control group, all indexes above changed insignificantly in the solvent group(P>0.05); the body weight increased, epididymal index reduced, the GSH level and GSH-Px activity decreased, MDA level increased, the ROS level in mature sperms increased, the survival rate of sperms reduced and its death rate increased, all with significant differenced(P<0.05). Compared with the model group, in the western medicine group, the body weight and epididymal index increased, the content of GSH and activity of GSH-Px increased, the levels of MDA and ROS decreased, and the survival rate of sperms significantly increased while the death rate of sperms reduced, all with striking differences(P<0.05). Compared with the western medicine group, in the Chinese medicine group, the body weight increased, the MDA content in epididymal tissue and ROS level in mature sperms significantly decreased, and the survival rate of sperms increased, all with significant differences(P<0.05).  Conclusion: New WSSJD can significantly relieve the oxidative injury in epididymis induced by cyclosporine and enhance the survival rate of mature sperms.