Objectives: The present study was designed to estimate serum and synovial fluid levels of osteopontin (OPN), tumor necrosis factor-α (TNF-α) and interleukin-6(IL-6) in patients with early rheumatoid arthritis, and evaluate their correlation with disease activity and relation to treatment. Patients & Methods: The study included 50 patients with early rheumatoid arthritis; 6 males and 44 females with mean age of 30.8±8 years ,mean disease duration 9 ± 1.3 month . All patients underwent complete clinical examination and Patients were categorized using DAS -28 as follow: Group I, 20 patients without disease activity (DAS< 3.2), Group II, 18 patients with moderate activity (DAS >3.2<5.1) and Group III, 12 patients with high activity (DAS > 5.1). Serum samples and synovial fluid(SF) of patients were obtained and estimated for levels of OPN, TNF-α, and IL-6. Patients received treatment for 3 months and postreatment samples were obtained to estimate the serum levels of these markers to evaluate their significance as indicators for treatment success. Control group were 20 post traumatic knee effusion blood samples and synovial fluid were obtained from them and compared with patients samples Results: Serum levels of estimated parameters were significantly higher in early rheumatoid patients compared to control levels. Also the estimated parameters in serum and synovial fluid were significantly higher in patients with higher disease activity than those without disease activity. Also there was significant difference in the above estimated parameters between pre and post-treatment samples levels. However, despite treatment induced significant decrease of samples levels of estimated parameters, their levels still significantly higher compared to control levels. Comparison of mean change percentage from pretreatment to post treatment showed highly significant difference as regard OPN while significant difference as regard TNF- α, and IL-6 Conclusion: Serum and synovial fluid OPN, TNF- α, and IL-6 are reliable markers for disease activity in patients with early rheumatoid arthritis. Also they are helpful to predict efficacy of treatment in those patients. OPN, showed the highest mean change in serum and synovial fluid post treatment and can be added as follow up parameter for early treatment efficacy Keywords: Early Rheumatoid arthritis, Osteopontin, tumor necrosis factor-α interleukin-6.