The aim of the study was to determine the thiol/disulfide homeostasis and oxidative stress parameter levels in sheep infected with pox virus and to investigate their diagnostic significance. 1-2 years old Morkaraman breed sheep (20 infected with pox virus, 10 healthy) were used in the study. Total thiol, native thiol, total antioxidant capacity (TAC) and total oxidant capacity (TOC) analyses were performed in sera obtained from blood samples taken from the jugular vein of the sheep in tubes without anticoagulant. When the pox virus infected group and healthy sheep were compared, it was determined that total thiol and native thiol levels were significantly decreased; disulfide, disulfide/native thiol and disulfide/total thiol levels increased but were not statistically significant. In addition, it was determined that serum TOC and oxidative stress index (OSI) levels increased, while TAC level decreased. In conclusion, the findings obtained in the study suggest that the disease causes oxidative stress, and the use of oxidative stress markers, especially thiol/disulfide homeostasis markers, may contribute to the pathogenesis of smallpox and be an auxiliary parameter for its diagnosis.