The collagen‐induced arthritis model in DA rats induced with homologous rat type II collagen was chosen to determine the therapeutic capacity and effects on autoimmunity by IL‐10. Systemic IL‐10 treatment (100 or 10 μg/day) with mini‐osmotic pumps during the periods of arthritis onset (days 12–20 after immunization) decreased the frequency of arthritis and delayed the onset and reduced the severity of arthritis in the few rats that eventually developed arthritis. Concomitantly, levels of autoantibodies to CII were reduced. To test the activity on established arthritis, IL‐10 was administered subcutaneously in the paws. This treatment reduced the swelling but did not block the arthritis process. The effective treatment required 100 μg of IL‐10 every 12th hour while 50 μg of IL‐10 had little effect, although a tendency of reduced paw swelling was observed. Surprisingly, therapeutic IL‐10 treatment led to higher serum levels of autoantibodies to CII. The highest doses of IL‐10 (100 μg) did not show any apparent toxic effects when given locally or systematically. Taken together, this study suggests that IL‐10 is a candidate for treatment of rheumatoid arthritis.