Objective <p>This study aims to assess the safety as well as effectiveness of Cilostazol as a complementary therapy to methotrexate among individuals with active rheumatoid arthritis.</p> Method <p>This study was a randomly allocated, double-blind, placebo-controlled parallel design involving 70 patients who were diagnosed with active rheumatoid arthritis. Participants were randomly assigned to two sets: the control group (<i>n</i> = 35) which received methotrexate "MTX" (7.5&#xa0;mg IM weekly) plus placebo tablets twice daily and the Cilostazol group (<i>n</i> = 35), which received the same MTX" dose plus Cilostazol 50&#xa0;mg twice daily&#xa0;for 3&#xa0;months. Patients were assessed to determine the serum levels of C-reactive protein (CRP) nuclear factor kappa B (NF-κB), hemoxygenase-1 (HO-1), and cyclic adenosine monophosphate (cAMP). Disease Activity Score (DAS28-CRP), Multidimensional Health Assessment Score (MDHAQ), and morning stiffness duration were also assessed.</p> Results <p>The Cilostazol group produced a significant improvement in cAMP level as compared to the control group (<i>P</i> = 0.001)<b>.</b> cAMP level showed a significant inverse correlation with DAS28-CRP (<i>r</i> = −0.336; <i>P</i> = 0.004). However, Cilostazol group produced non-significant improvements in the serum levels of the other biological markers (CRP, NF-κB, and HO-1), DAS28-CRP score, MDHAQ score, and morning stiffness duration as compared to the control group (P &gt; 0.05). The implication of Cilostazol for patients with rheumatoid arthritis was tolerable and safe.</p> Conclusion <p>The beneficial effect of Cilostazol on cAMP and the negative correlation between cAMP and DAS28-CRP could support its impact on the disease activity. Further research seems necessary to elucidate the mechanisms underlying the link between cAMP and disease activity.</p> Trial registration <p>Clinical Trials.gov identifier: NCT05594680<b>,</b> The date of registration is: 30/10/2022.</p>