INTRODUCTION: Osteoarthritis (OA) is the most common degenerative joint disease, and its aetiology is not entirely known. The aim of the study was to evaluate the involvement of interleukin-18 (IL-18) and interleukin-20 (IL-20) in the pathogenesis of knee OA and their correlations with other markers of inflammation and destruction of joint cartilage, as well as clinical and radiological changes. MATERIAL AND METHODS: The study included 25 patients with knee OA and a control group. The concentration of IL-18, IL-20, IL-6, MMP-1, MMP-3, COMP, PG-AG, and YKL-40 in serum and synovial fluid (SF) were determined. We also evaluated radiological lesions of the knee joint according to the Kellgren-Lawrence (K-L) scale, and clinical severity of the disease according to Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Lequesne Index. RESULTS: The concentrations of IL-18 and IL-20 were statistically significantly higher in serum of patients with OA than in the control group (106.00 ±189.76 pg/ml vs. 16.73 ±16.99 pg/ml, < 0.001, 17.69 ±13.45 pg/ml vs. 9.76 ±9.00 pg/ml, < 0.014). Serum concentration of IL-18 positively correlated with MMP-3 ( = 0.58; = 0.006) and YKL-40 ( = 0.48; = 0.002). The degree of radiological advancement of OA (K-L scale) correlated positively with clinical evaluation (WOMAC, = 0.74, ≤ 0.001; Lequesne Index, = 0.57, = 0.003). CONCLUSIONS: The analysis of ROC curves showed that IL-20 as well as COMP, MMP-3, and YKL-40 may be diagnostic markers of knee OA. The observations indicate that IL-18 potentially mediates mainly in intra-articular processes and IL-20 could be primarily responsible for the systemic inflammatory reaction.