Introduction: Diabetic nephropathy (DN) is one of the diabetic complications, which leads to end-stage renal disease. This study aimed to assess the expression of the lipoic acid synthetase (LIAS) gene in type 2 diabetic patients and DN patients. Subjects and Methods: A case-control study conducted on 60 patients who had type 2 diabetes, 60 patients who had DN, and 60 healthy matched individuals. The peripheral blood expression of the LIAS gene was assessed by real-time qRT-PCR. Results: In diabetic and DN patients, the expressions of LIAS were significantly lower than controls (p < 0.001). The LIAS expression showed a reducing trend with the progress of DN (p < 0.001). The LIAS expression showed a sensitivity of 95 % and specificity of 88.3% in the differentiating between diabetic and DN patients and it can detect early DN with a sensitivity of 93.5 % and specificity of 90%. LIAS expression in DN patients had significant negative correlations with disease duration and albuminuria. LIAS gene expression can protect significantly from the DN. It had an odds ratio of 0.01 [95% confidence interval (CI): 0.001-0.03] (p < 0.001). LIAS gene expression can significantly predict disease severity. Conclusion: Peripheral blood expression of the LIAS gene was significantly lower in diabetic and DN patients in comparison to controls. The LIAS expression negatively correlated with the progress of DN. LIAS gene expression seems to be a promising marker for prediction and early detection of DN in type 2 diabetic patients.