Avermectins including Ivermectin and Eprinomectin are broad spectrum endectocides. These drugs are considered to have no serious adverse effects at therapeutic range. However, use of avermectins in overdose in some animal species and at the therapeutic range in humans could result in some adverse effects including mainly nervous system effects and some general symptoms. This study was aimed to investigate effects of Eprinomectin and Ivermectin on plasma malondialdehyde (MDA) and glutathione (GSH) levels in lactating cow. Ten Holstein breed lactating dairy cows were divided into 2 groups. Before the application of drugs, blood samples were collected from the jugular vein in each group at 0 hour as control, and then Group 1 and 2 received a single pour-on application of Ivermectin (0.5 mg/kg body weight) and Eprinomectin (0.5 mg/kg body weight), respectively. Blood samples were then collected again from the jugular vein at timed-intervals (at 1, 4, 8, 24 and 36 hours and on 2, 3, 4, 5, 6, 8, 10, 12, 15, 20 and 25th days) to measure plasma MDA and GSH concentrations. Eprinomectin and Ivermectin treatment caused a transient decrease in GSH levels which is followed by transient increase (P < 0.05). However, no difference was observed in MDA levels at all sampling points following the Eprinomectin and Ivermectin treatment compared to control samples (P > 0.05). It was concluded that Eprinomectin and Ivermectin cause decreased GSH concentrations without alterations in MDA level leading to a decrease in the defense mechanism against oxidative stress although the decrease is not enough to cause lipid peroxidation.