Background: Rheumatoid arthritis (RA) is a common autoimmune disease, however, despite decades of research, the etiology and pathogenesis of RA remain unresolved. The increased levels of Myeloperoxidase (MPO) found in various inflammatory diseases have led to the hypothesis that MPO-mediated pathophysiological reactions are causally implicated in driving the disease process. Aim: at investigating the potential utility of the MPO as a biomarker of inflammatory disease activity in RA patients, through the assessment of plasma and synovial fluid levels of MPO in RA patients and its correlation with disease activity. Subjects and Methods: The current study was a case-control study, performed at the Physical Medicine, Rheumatology, and Rehabilitation department at Suez Canal University Hospital and Ismailia General Hospital on 66 participants; 33 patients and 33 controls, to assess the correlations between MPO levels (in plasma and synovial fluid) and disease activity of RA through the disease activity score and the ACR Classification of Global Functional Disability Status in RA. Results: Study results showed that the plasma MPO level in RA patients was significantly higher than in their controls. Both plasma and synovial MPO shows significant positive correlations with the duration of the disease. Both plasma and synovial MPO show a significantly large area under the curve (0.688 and 0.952, respectively), denoting a high diagnostic performance. Conclusions: RA patients had significantly elevated levels of plasma and synovial MPO, which were significantly correlated with disease activity. Both plasma and synovial MPO showed substantial diagnostic performance for disease activity.