Objective To determine the ability of grape seed proanthocyanidin extract(GSPE) in alleviating arsenic-induced reproductive toxicity. Methods Sixty male Kunming mice received the following treatments by gavage: normal saline solution(control); arsenic trioxide(ATO; 4 mg/kg); GSPE(400 mg/kg); ATO+GSPE(100 mg/kg); ATO+GSPE(200 mg/kg) and ATO+GSPE(400 mg/kg). Thereafter, the mice were sacrificed and weighed, and the testis was examined for pathological changes. Nuclear factor(erythroid-derived 2)-like 2(Nrf2), heme oxygenase 1(HO1), glutathione S-transferase(GST), NAD(P)H dehydrogenase, and quinone 1(NQO1) expression in the testis was detected by real-time PCR. Superoxide dismutase(SOD), glutathione(GSH), total antioxidative capability(T-AOC), malondialdehyde(MDA), 8-hydroxydeoxyguanosine(8-OHd G), and reproductive indexes were analyzed. Results ATO-treated mice showed a significantly decreased sperm count and testis somatic index and activity levels of SOD, GSH, and T-AOC than control group. Compared to the ATO-treated group, ATO +GSPE group showed recovery of the measured parameters. Mice treated with ATO+high-dose GSPE showed the highest level of m RNA expression of Nrf2, HO, NQO1, and GST. Conclusion GSPE alleviates oxidative stress damage in mouse testis by activating Nrf2 signaling, thus counteracting arsenic-induced reproductive toxicity. Methods Sixty male Kunming mice received the following treatments by gavage: normal saline solution (control); arsenic trioxide (ATO; 4 mg / kg) ; GSPE (400 mg / kg); ATO + GSPE at 100 mg / kg; ATO + GSPE at 200 mg / kg and ATO + GSPE at 400 mg / kg After the mice were sacrificed and weighed, and the Nuclear factor (erythroid-derived 2) -like 2 (Nrf2), heme oxygenase 1 (HO1), glutathione S-transferase (GST), NAD (P) H dehydrogenase, and quinone 1 (NQO1) expression in the testis was detected by real-time PCR. Superoxide dismutase (SOD), glutathione (GSH), total antioxidant capability (T-AOC), malondialdehyde (MDA), and reproductive indexes were analyzed. Results ATO-treated mice showed a significant decreased sperm count and testis somatic index and activity levels of SOD, GSH, and T-AOC than control gr Moup treated with ATO + high-dose GSPE showed the highest level of m RNA expression of Nrf2, HO, NQO1, and GST. Conclusion GSPE alleviates oxidative stress damage in mouse testis by activating Nrf2 signaling, thus counteracting arsenic-induced reproductive toxicity.