Aggrecan and cartilage oligomeric matrix protein (COMP) which are important degradation products of articular cartilage may be promising diagnostic markers in serum and/or synovial fluid for diagnosis of knee osteoarthritis (OA). Our objective was to measure serum and synovial fluid levels of aggrecan and COMP in patients with OA of the knee joint to find out if they could be of diagnostic value in OA and if their levels correlate with the clinical and radiological manifestations of the disease. Sixty-six patients suffering from primary knee OA with effusion (26 males and 40 females) were studied. Twenty individuals (six males and 14 females) with recent traumatic knee effusion matched for age and sex were chosen to serve as a control group. All subjects had thorough clinical and radiological (X-ray and MRI) evaluation. Aggrecan and COMP in serum and synovial fluid were measured by ELISA. Serum and synovial fluid aggrecan and COMP levels were significantly higher than the control. Serum and synovial fluid aggrecan and COMP levels were positively correlated with age, body mass index, disease duration, plain X-ray and MRI scores. In OA, serum and synovial fluid aggrecan and COMP levels are elevated and represent useful markers in the diagnosis. Moreover, these elevated levels positively correlated with radiological joint damage but not with clinical disease parameters. These markers have the potential to be used for monitoring articular cartilage destruction and response to different therapeutic modalities.