This is the first demonstration of a role for type II collagen in pristane-induced arthritis. Pretreatment with soluble type II collagen either lowers or raises the subsequent incidence and severity of pristane-induced arthritis. These effects are dependent upon both the dose and route of administration of the soluble type II collagen. Increasing doses of orally administered type II collagen lowered both the incidence and severity of pristane-induced arthritis. Conversely, increasing doses of intraperitoneally administered type II collagen increased both the incidence and severity of arthritis. This exacerbation of pristane-induced arthritis was accompanied by elevated B- and T-cell responses to type II collagen. These findings highlight the importance of the site at which antigen is encountered in influencing subsequent immune responses and extend the observations of the use of orally administered antigens to ameliorate experimental autoimmunity.