The presence of immune reactivity to collagen in patients with rheumatoid arthritis as well as recent interest in the type II collagen-induced arthritis model have suggested a role for autoimmunity to collagen as a major disease mechanism. However, data concerning the occurrence of antibodies (AB) against the different types of collagen during a spontaneously occurring, histologically well-defined arthritis have been lacking. Sera from 48 MRL I mice aged 5 to 25 weeks with spontaneously occurring hindlimb arthritis were obtained. Sera were tested for auto-AB against collagens utilizing highly purified native collagen types I-VI. Significant levels of circulating AB against native collagen types I, III, and VI could not be detected in any age group. The greatest elevation of antibodies directed against type II collagen was found in 13- to 15-week-old mice. AB against type IV collagen were detected in slightly elevated levels with a maximum at 9-10 weeks. Most strikingly, AB against type V were markedly elevated after 19 weeks. The occurrence of high levels of AB against type V collagen, largely found in the pericellular matrix of smooth muscle cells, is associated with the late stage of disease characterized by histologically documented vasculitis. The results suggest that AB to collagen occur as a consequence of tissue destruction and that evidence for a pathogenetic role of AB in MRL I arthritis is lacking. © 1987.