Relapsing polychondritis is a systemic disease associated with a destruction of cartilage in various parts of the body. Sera from six patients with relapsing polychondritis and one patient with microscopic polyarteritis nodosa as well as from six controls were analyzed by immunoblotting and ELISA. All patients had autoantibodies against native collagens II and IX. The serum from one patient showed a strong reaction with all three collagen chains of the high molecular weight fraction of collagen IX after denaturation; sera from four patients showed autoantibodies against alpha 2 (XI) and sera from three patients showed autoantibodies against the covalently cross-linked gamma component of collagen XI. The presence of autoantibodies against collagens II, IX, and XI, which form the major fibrillar scaffold in cartilage and mediate the interaction of collagen fibrils and proteoglycan, suggests that autoantibodies against cartilaginous collagen may play a crucial role in the pathogenesis of relapsing polychondritis and microscopic polyarteritis nodosa.