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Background: In recent years, considerable attention has been paid to the role of microRNAs (miRs) as biomarkers in type 2 diabetes (T2D). The aim of the study was to evaluate the expression levels of miR-15a and miR-222 in diabetic, pre-diabetic, and healthy individuals., Materials and Methods: Ninety individuals, who were referred to the Yazd diabetic center, were enrolled in this study and then classified into three groups as healthy, pre-T2D, and diabetic based on the clinical manifestations. Real-time PCR was performed to explore miRs expression in the plasma samples of the studied population. The correlation between the biochemical characteristic and the expression of these miRs as well as specificity and sensitivity of different clinical markers in healthy and pre-diabetic groups was evaluated., Results: miR-222 expression was significantly upregulated in the pre-T2D cases compared to the control subjects (P<0.001), while no significant difference was found between the pre-T2D and T2D groups (P<0.05). The expression of miR-15a was statistically downregulated in the pre-T2D and T2D subjects (P<0.05). The receiver operating characteristic (ROC) curve analysis of miR-15a expression with a cutoff point of 1.12 resulted in the area under the curve (AUC) of 85% (95% CI 0.865-0.912; P<0.001) with 84% and 85% sensitivity and specificity, respectively. Similarly, for miR-222, the cutoff point of 4.03 and AUC of 86% (95% CI 0.875-0.943; P<0.001) discriminated against the pre-T2D and control subjects via the sensitivity and specificity of 86% and 87%, respectively. Moreover, miR-15a values showed a negative correlation with FG (R=-0.32, P=0.005); however, miR-222 values were positively correlated with FG (R=0.25, P=0.03) in the pre-T2D group. Furthermore, miR-222 values were correlated with OGTT in the pre-T2D group (R=0.27, P=0.001). In addition, LDL-C had a negative correlation with miR-222 values in the pre-T2D group (R=-0.23, P=0.02)., Conclusion: This study indicated that the plasma expression levels of miR-222 and miR-15a can be considered as non-invasive, fast tools to separate the pre-T2D individuals from their healthy counterparts. Accordingly, this information could be used to predict the development of the disease as well as a direction for optimal therapy, thus refining outcomes in patients with diabetes., Competing Interests: The authors declare that they have no conflicts of interests., (© 2020 Sadeghzadeh et al.)