Hyperglycemia is one of the most important factors that are responsible for oxidative stress and production of reactive oxygen species (ROS) in diabetes. Proteins are likely to be major targets of ROS, as a result of their abundance in cells, plasma, and most tissues, and their rapid rates of reaction both with many radicals and with other oxidants. Proteins that are damaged by oxidative stress have decreased biological activity leading to loss of energy metabolism, cell signaling, transport, and, ultimately, to cell death. Protein carbonyl content is the most general and well-used biomarker of severe oxidative protein damage. Aims: To investigate the relationship between serum protein carbonyl content, total thiol and glycated hemoglobin (HbA_1c) in Egyptian patients with type 2 diabetes mellitus under poor glycemic control. Methods: Fifty patients with type 2 diabetes mellitus were recruited from the department of Internal medicine, Sohag University Hospital, Egypt and 20 age- and sex-matched healthy controls. Serum protein carbonyl content, total thiol and HbA_1c were measured. Results: The study revealed that serum protein carbonyl content in diabetic patients was significantly higher than the controls (19.9 ± 5.3 vs. 2.43 ± 1.5 nmol/L, P < 0.001), while total thiol was significantly lower in the patients than the controls (193 ± 50.6 vs. 298 ±78.5 μmol/ml, P < 0.001). Protein carbonyl content was negatively correlated to total thiol, positively correlated to HbA_1c and total thiol was negatively correlated with HbA_1c. Conclusions: Hyperglycemia is associated with an increase in the protein oxidation in terms of an increase in protein carbonyl content and a decrease in total thiol group. Therefore, poorly controlled diabetic patients may be subjected to numerous pathological conditions related to the increased protein oxidation.