YKL-40 is a newly discovered major secretory protein of human chondrocytes and synoviocytes. We measured serum levels of YKL-40 in 52 patients with early onset rheumatoid arthritis (RA) by enzyme-linked immunosorbent assay (ELISA) during a 2-year prospective follow-up, correlating values with laboratory and clinical variables and radiographic progression. Levels at baseline before antirheumatic therapy were significantly higher in patients than in healthy controls. The levels of YKL-40 correlated with laboratory and clinical markers of disease activity both at baseline and during follow-up. Baseline YKL-40 values correlated with baseline Larsen scores but did not predict radiographic progression. Baseline and mean YKL-40 values did not differ between fast and slow radiological progressions. Mean YKL-40 levels correlated with the number of swollen joints but were not predictors of radiographic progression. These results suggest that in early RA, serum YKL-40 is an inflammatory marker correlating with disease activity. However, its levels do not predict clinical course or radiographic progression.