Oxidative damage has been implicated to be one of main mechanisms by which fluoride (F) induces toxic effects. Previous studies reported that F destroyed the epididymal structure of mouse and rabbit. Epididymis is the important place for sperm maturation. However, little is known about the effect of F on the oxidative stress status of epididymis. Therefore, the aim of the present study was to explore the changes in the activities and transcriptional levels of CuZn superoxide dismutase (CuZn-SOD, SOD1) and catalase (CAT), as well as the ultrastructure, in testis and epididymis of mice administrated with F. Sixty health Kunming mice were randomly divided into four groups. With one group untreated as controls, the others were treated with 25, 50, and 100 mg NaF/L in drinking water. After 10 weeks administration, mitochondrial ultrastructural changes in testis and epididymis were observed, including the incomplete membrane and the dissolved or disappeared cristae. Compared to the control group, the activities of both SOD1 and CAT in testis and epididymis were significantly reduced by 50 or 100 mg NaF exposure. In addition, the mRNA expressions of testicular SOD1 and CAT were also decreased significantly in 100 mg NaF/L group, while the SOD1 and CAT mRNA expressions in epididymides were significantly reduced in all F treatment groups. The above results suggest that in the presence of F, similar to testis, epididymis also loses the balance between oxidative stress and antioxidative defense, and perhaps more sensitive to F.