Objectives: The current work was designed to assess the roles of IL-21, IL-17, CD163, and hs-CRP in the activity of osteoarthritis of Iraqi patients. Patients and Methods: Sixty (60) patients with age groups ranging from (45 -70) years suffering from knee osteoarthritis were involved in this work. Any gender with age > 45 years with knee pain. Patient's diagnosis with KOA according to the American College of Rheumatology (ACR) reviewed criteria of early diagnosis of KOA. Data collection Age, gender, body mass index, disease duration, disease severity and medication were collected from all patients. Sixty (60) apparently healthy volunteers without a previous history of knee osteoarthritis and any of the exclusion criteria were selected from our population as the control group. Three milliliters (3ml) of peripheral blood were obtained via venipuncture and poured into a plain gel tube to separate the serum. Serum specimens were kept in tubes at -20°C to be used for detection of these markers by Sandwich ELISA technique. Results: The mean levels of hs-CRP, CD163, and IL-17 were significantly higher in Knee osteoarthritis patients when compared with healthy controls (5.71 mg/dl vs 0.84 mg/dl, P= 0.001; 60.81 ng/ml vs 48.53 ng/ml, P= 0.001; and 177.2 pg/ml vs 30.29 pg/ml, P= 0.003, respectively). On the other hand, no significant difference (P ≥ 0.05) was found in the mean levels of IL-21 between the two studied groups.  There is a relation only between IL-17 and hs-CRP with the severity of the disease, this is indicated by P-value (0.001 and 0.009) respectively.Conclusion:This study concludes that levels of some immunological markers were elevated in osteoarthritis patients as IL-17, hs-CRP and CD163. IL-17 and hs-CRP levels were higher in grades 4 and 3 than in grade 2 and, therefore can be considered as an indicator of the severity of this disease.