The aim of this study was to investigate the possible protective role of caffeic acid phenethyl ester on testicular toxicity of methotrexate in rats. Nineteen male rats were divided into three groups as follows: group I, control; group II, methotrexate-treated; group III, methotrexate + caffeic acid phenethyl ester-treated. In the second day of experiment, a single dose of methotrexate was intra-peritoneally administered to groups II and III, although a daily single dose of caffeic acid phenethyl ester was intra-peritoneally administered to group III for 7 days. At the end of the experiment, the testes of the animals were removed and weighed. In the tissue, the level of lipid peroxidation as malondialdehyde and activities of superoxide dismutase were higher in the methotrexate group than in the control group. Lipid peroxidation levels and superoxide dismutase activities were decreased in caffeic acid phenethyl ester + methotrexate group compared with methotrexate group. The activities of catalase in the methotrexate group decreased insignificantly although its activities were significantly increased by caffeic acid phenethyl ester administration. The activity of glutathione peroxidase did not change in the groups. There was significant difference in body weight between control and methotrexate-induced groups. In conclusion, the administration of methotrexate causes elevation of oxidative stress although treatment with caffeic acid phenethyl ester has protective effects on the oxidative stress in testes.