Rheumatoid arthritis (RA) is a chronic symmetric polyarticular arthritic disease characterized by symptoms of inflammation and pain in the joints. It was reported that some miRNAs are markedly dysregulated in RA. So, this study was aimed to identify the expression pattern of miR-96-5p and miR-298 as diagnostic biomarkers for RA and to see how patients with early RA respond to therapy based on that pattern. This study was conducted on 120 individuals enrolled from the outpatient clinic of El Hussein University Hospital. They were divided into three groups; early diagnosed (ERA) patients, methotrexate (MTX) -treated RA patients for 6 months, and healthy controls (HC). Total RNA was extracted from entire sera and the expression of miR-96-5p and miR-298 was analyzed by Real-Time Quantitative polymerase chain reaction (qRT-PCR). Receiver operating characteristic (ROC) curve analyses were conducted for miR-96-5p and miR-298 in the diagnosis of RA and the prediction of therapeutic efficacy in MTX -treated RA patients. In our current study we reported that miR-96-5p and miR-298 levels were significantly higher in ERA patients in comparison with healthy participants. And interestingly, both of them were down-regulated in MTX-treated RA patients. Moreover, study illustrated that they could be used as a RA biomarker for the diagnosis and also for the prediction of therapeutic efficacy in MTX -treated RA patients.