The results of previous studies regarding the role of adiponectin in the pathogenesis of osteoarthritis (OA) are controversial. The aim of this study is to investigate the relation of plasma adiponectin levels with clinical and radiological disease severity in knee OA patients. Sixty patients with knee OA and 25 healthy controls were included in the study. Patients were divided into two subgroups: lean (Group 1, n = 30) and obese (Group 2, n = 30). Healthy controls were accepted as Group 3 (n = 25). Pain intensity was measured with a visual analogue scale (VAS), functional disability with Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and Quality of Life (QoL) with Short Form-36 (SF-36). Also all patients were radiologically evaluated and graded according to Kellgren-Lawrence (KL) scale. Plasma concentrations of adiponectin levels were measured by enzyme-linked immune-sorbent assay (ELISA). Serum adiponectin levels were higher in OA patient subgroups than those in the control group but the difference did not reach a significant level after adjustments for age, gender and body mass index (P = 0.078). There was a positive correlation between adiponectin concentration and KL grading scores. Additionally, there was a positive correlation between adiponectin levels and clinical variables (VAS and WOMAC total scores) in patient subgroups (r = 0.326 P = 0.012, r = 0.583 P < 0.001, respectively). SF-36 scores were inversely associated with adiponectin levels. Plasma adiponectin concentrations were associated with both clinical and radiological disease severity in knee OA patients. Thus, adiponectin hormone might be a potential clinically useful biomarker while assessing disease severity in the future.