BackgroundThe plans for the successful treatment of rheumatoid arthritis (RA) seek to attain low disease activity or reach clinical remission. ObjectiveOur study aimed to compare the serum MMP-3 levels with predictors of response to therapy of rheumatoid arthritis in Syrian patients and explore its worth as a new valuable biomarker for RA therapy outcomes in daily practice. MethodsSerum samples were gathered from 43 RA patients at diagnosis and 12 weeks of therapy. Related clinical and laboratory tests were estimated, levels of serum MMP-3 were measured by ELISA method and the disease activity was assessed using disease activity scores in 28 joints with an erythrocyte sedimentation rate (DAS28-ESR) before and after therapy. ResultsThe mean of Serum MMP-3 levels significantly decreased (322.3 ± 43.83 ng/ml) after therapy (12 weeks) in RA patients compared to its mean at baseline (486.49 ± 34.5 ng/ml). There wasn't a statistically significant difference in the mean of MMP-3 levels before and after therapy (P = 0.137) in non-responder patients. Patients who showed a good response (N = 38) presented higher MMP-3 levels at first which subsequently decreased significantly at the 12-week follow-up (P < 0.05). Also, there was a statistically significant difference in MMP-3 levels between the two groups of patients after therapy (P = 0.002). To differentiate between RA patients who responded to therapy and who did not, our results found that the cut-off value of serum MMP-3 was 317.8 ng/ml (sensitivity was 80%, specificity was 73%, AUC was 0.818, 95% CI: 1.114–112.5; P = 0.045) and the best cut-off value of DAS28-ESR was 5.325 (sensitivity 100%, specificity 100%, AUC = 100%,95% CI: 15.2 to 47203.8). Conclusionserum MMP-3 can be added as a novel and valuable biomarker in estimating the therapeutic response in RA patients, but it isn't better than DAS28-ESR.