We compared the ability of assay for cross-linked carboxyterminal telopeptide of type I collagen (ICTP) and CrossLaps assay to reflect increased pathological degradation of type I collagen in serum and synovial fluid samples of patients with rheumatoid arthritis (RA; n = 40). ICTP and CrossLaps concentrations were correlated with each other and with markers of collagen synthesis (PINP and PIIINP, amino terminal propeptides of type I and type III procollagens, respectively) and with markers of inflammation, i.e., C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). Serum ICTP was increased in half of the RA patients, whereas CrossLaps assays were increased only occasionally. Serum ICTP correlated with the other markers of collagen metabolism as well as with CRP and ESR. Serum CrossLaps correlated only with PINP and ICTP, but not with serum PIIINP, CRP or ESR. Two patients had false-positive reactions in the CrossLaps assay due to the rheumatoid factor. The ICTP and CrossLaps antigens were clearly separate peaks in gel filtration analysis. The CrossLaps assay is able to detect the same ICTP antigen, but not vice versa. The ICTP assay reflects increased matrix metalloproteinase-mediated collagen degradation in joints in RA. In contrast, the physiological cathepsin K-mediated bone resorption measured by the CrossLaps assay was only occasionally increased.