Background: type 2 diabetes mellitus (T2DM) has reached epidemic proportions worldwide, coronary artery disease (CAD) are one of the most important causes of mortality worldwide. MicroRNAs (miRNAs) modulate gene expression and involved in the pathogenesis of T2DM and CAD. The objective of the current study was to explore the expression pattern of miR-122 in T2DM with or without CAD. Also, we aimed to evaluate the association between miR-122 with risk and severity CAD of in T2DM. Methods: This crosssectional controlled study enrolled 130 patients with T2DM and 110 control group. The enrolled diabetic patients classified into two groups: seventy patients without CAD and 60 patients without CAD. All patients investigated using a 12- lead standard ECG, echocardiography and coronary arteriography. The serum MiR- 122 expression profile measured using quantitative real time-polymerase chain reaction (qRT-PCR). Results: miRNA-122 expression levels were significantly higher in T2DM in particular T2DM patients with CAD compared to the control group. Interestingly, miRNA-122 expression levels were positively correlated with cardiometabolic risks and severity of coronary occlusion. Linear regression analysis test showed that miRNA-122 were independently correlated with HDL, ejection fraction and uric acid. The power of miRNA-122 expression level to diagnose T2DM among studied subjects was evaluated using Receiver operating characteristic (ROC). The area under curve (AUC) was 0.997 (95% CI = 0.993–1.00) with sensitivity = 96.9%, specificity = 99 % and the power for differentiating T2DM with CAD from T2DM patients without CAD the AUC was 0.832 (95% CI = 0.763–0.902) with sensitivity = 93.3%, specificity = 96.86.Conclusion: The miRNA-122 expression levels were higher in the T2DM group compared to controls in particular patients with CAD. The higher levels of miR-122 expression levels were strongly correlated with cardiometabolic risk factors and severity of coronary occlusion. Therefore, miR-122 expression levels seem to be the anon invasive biomarker of the CAD