Complement activation has been implicated in the pathogenesis of human rheumatoid arthritis. We sought to determine whether inhibition of complement (C) using sCR1 could influence the development and progression of antigen arthritis in the rat, a recognized model of human chronic synovitis. The effect of C inhibition, systemically and locally, on three different stages of disease was examined: (i) prophylaxis, (ii) treatment of established inflammation, and (iii) prevention of antigen-induced flares of disease. Arthritis was assessed by knee swelling and by histological examination. Our results show that intra-articular injection of sCR1 prior to disease onset reduced joint swelling and development of arthritis, whereas systemic administration was ineffective. Treatment of established arthritis with intraarticular sCR1 3 days after disease onset caused a transient reduction in swelling, but treatment 7 days after disease onset had no effect on disease. An intra-articular dose of sCR1 given at the time of disease flares had a small, yet significant effect on knee swelling. We conclude that complement activation is important in the initiation and maintenance of inflammation in antigen arthritis. The potent effect of local C inhibition suggests that C biosynthesis and activation within the joint contributes to inflammation in this model of arthritis.