Background: Rheumatoid arthritis (RA) is a chronic inflammatory disorder, which is associated with joint deformity and functional impairment. Paradoxically, the pathogenesis of RA adiponectin appears to have proinflammatory activities in the joints, being able to induce the release of inflammatory mediators and may also be linked to disease activity. Objective: To assess serum concentration of high-molecular-weight APN (HMW-APN) in RA cases and its association with disease activity. Methods: This cross sectional case-control study included 80 persons that were divided into 2 groups; group A (patients' group) that involved 40 RA cases and group B that included 40 normal persons with matched age and sex. Serum level of high-molecular-weight adiponectin was assessed using ELISA technique. Plain X-ray on both hands to detect bone erosion was assessed by Larsen Score. Results: Serum levels of HMW-APN were significantly higher in RA cases in comparison with controls. A significant positive correlation existed between HMW APN with number of swollen joints and Disease Activity Score-28 for Rheumatoid Arthritis with ESR (DAS28-ESR), ESR, Rheumatoid factor, anti-cyclic citrullinated peptides (CCP) antibodies and Larsen Grading Scale. According to the ROC analysis, the best cutoff point of serum HMW-APN to identify RA from healthy control was > 77.04 Pg/ml. This point showed high sensitivity (87.5%) with moderate specificity (70%) and AUC (0.883). Conclusion: Serum levels of HMW-APN could be used as reliable biomarker in diagnosis of RA in addition to determination of the disease activity.