AIM: To compare the effects of thiamine pyrophosphate (TPP) and thiamine (TM) in oxidative optic neuropathy in rats induced by ethambutol. METHODS: The animals were divided into four groups: a control group (CG), an ethambutol control (ETC) group, TM plus ethambutol group (TMG), and TPP plus ethambutol group (TPPG). One hour after intraperitoneal administration of TM 20 mg/kg to the TMG group and TPP 20 mg/kg to TPPG group, 30 mg/kg ethambutol was given via gavage to all the groups but the CG. This procedure was repeated once daily for 90d. After that period, all rats were exposed to high levels of anaesthesia in order to investigate the gene expression of malondialdehyde and glutathione in removed optic nerve tissue and histopathologically to examine these tissues. RESULTS: Malondialdehyde gene expression significantly increased, whereas glutathione gene expression significantly decreased in the ETC group compared to the CG. TM could not prevent the increase of malondialdehyde gene expression and the decrease of glutathione, while TPP significantly could suppress. Histopathologically, significant vacuolization in the optic nerve, single-cell necrosis in the glial cells, and a decrease in oligodendrocytes were observed in the ETC group. Vacuolization in the optic nerve, a decrease in oligodendrocytes and single-cell necrosis were found in the TMG group, while no pathological finding was observed in the TPPG group except for mild vacuolization. CONCLUSION: TPP protects the optic nerve against the ethambutol-induced toxicity but TM does not. TPP can be beneficial in prophilaxis of optic neuropathy in ethambutol therapy.