Objective: Interleukin-6 (IL-6) is a key cytokine in rheumatoid arthritis pathogenesis. We aimed to analyze the association between IL-6 serum levels and joint inflammation at baseline and the correlation of time-integrated IL-6 values with structural damage during the first 36 months of early arthritis. Methods: IL-6 was assessed by 2 different methods in 813 patients of the French early arthritis cohort ESPOIR (Etude et Suivi des Polyarthrites Indifférenciées Récentes) over 36 months. IL-6 and C-reactive protein (CRP) changes were correlated to radiographic progression assessed by the total Sharp/van der Heijde score (SHS). Synovium inflammation was assessed in a subgroup of 126 patients by ultrasonography (US). The relationship between SHS change and IL-6 or CRP levels at baseline was investigated by a univariate regression and a multivariable analysis. A longitudinal model nested by visit and patient was conducted to assess the role of IL-6 on SHS at each visit. Results: At baseline, IL-6 was more strongly correlated with the swollen joint count than CRP level. In the univariate analysis, the time-integrated value of IL-6 was more strongly correlated with the swollen joint count and the variation of SHS than time-integrated CRP level. Baseline IL-6 was not independently associated with SHS change. Longitudinal models nested by patient showed that IL-6 levels were associated with structural damage independently from the Disease Activity Score in 28 joints, smoking status, rheumatoid factor, and anti-citrullinated protein peptide antibody serology, treatments, and CRP levels. Conclusion: IL-6 level was a marker of US synovitis at baseline. Repeated measurements of IL-6 are associated with structural damage.