Evidence showed that chronic inflammatory and immunopathological responses play a pivotal role in the development of osteoarthritis (OA). Interleukin-38 (IL-38) as a novel anti-inflammatory cytokine with influential modulatory properties on both innate and adaptive immune responses can be involved in the pathogenesis of OA. Therefore, this study aimed to measure the serum level of IL-38 in OA patients to clarify the positive or negative association with disease and its severity. Blood specimens were collected from two groups including 23newly-diagnosed OA patients and 22 healthy sex and age-matched subjects as a control group. Serum IL-38 quantities were measured using enzyme-linked immunosorbent assay (ELISA). Significantly higher IL-38 levels were detected in OA patients in comparison with the healthy group (265.78±41.27 pg/mL vs 44.23±6.04 pg/mL, p=0.0001). The IL-38 concentration in OA patients with Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores>40 and in OA patients with visual analog scale (VAS) scores >5 werehigher than those with WOMAC scores<40, and VASscores<5 (p=0.026 and p=0.035, respectively). The IL-38 levels in OA patients with body mass index (BMI)25 (p=0.05). According to our findings, WOMAC, VAS, and BMI indices may influence the IL-38 serum levels in OA patients and it may be elevated in OA patients to modulate inflammatory responses in a compensatory manner.The patients with OA, especially those with more severe disease express higher serum amounts of IL-38. Accordingly, IL-38 may be considered as a valuable marker for OA.