Objective: To assess the relationship of biochemical markers and radiographic signs of osteoarthritis (ROA) in the subjects with symptomatic osteoarthritis (OA) at multiple sites of the Genetics osteoARthritis and Progression (GARP) study. Methods: We have measured eight biochemical markers, representing tissue turnover of cartilage, bone, synovium, and inflammation. ROA was assessed in the knees, hips, hands, vertebral facet joints and spinal disc degeneration (DD) by using the Kellgren score. A proportionate score was subsequently made for each joint location based on the number of joints with ROA. Principal component and linear mixed model analyses were applied to analyze the data. Results: Three different clusters of markers were identified that may reflect different pathophysiological processes of OA. The first component appeared to be reflected by structural markers of cartilage and bone turnover and associated especially in subjects with hip ROA. The second component was reflected by a marker of inflammation and was associated with knee ROA, high Western Ontario and McMaster Universities (WOMAC) scores and body mass index (BMI). The third component included markers of cartilage turnover and was associated with ROA at hands, spine as well as age. High familial aggregation was observed for serum cartilage oligomeric matrix protein (S-COMP) (70%) and serum N-propeptide of collagen type IIA (S-PIIANP) (62%). Conclusion: Using a large well-characterized study and eight biochemical markers, we were able to observe three components that may reflect different molecular mechanisms (bone, cartilage, synovium turnover and inflammation). Our data suggested that these components contribute differently to ROA at different joint sites. © 2006 Osteoarthritis Research Society International.