We evaluated the cellular and humoral immune response to type II collagen and the relative susceptibility to type II collagen-induced arthritis (CIA) in 14 inbred rat strains representing six RT1 specificities and including four congenic strain pairs differing only at RT1, by using a standard protocol with native calf type II collagen as the immunogen: WF(RT1u) was a high responder and susceptible; RT1c , RT1a , and RT1l strains were intermediate responders and, on a strain basis, were variably susceptible or resistant; RT1b and RT1n strains were low responders and resistant to CIA. An intermediate to high immune response to type II collagen, although associated with CIA, was not sufficient for the induction of clinical arthritis. A high degree of cross-reactivity between calf and rat type II collagen was found. No selective, antigen-specific decrease in immune response to rat type II collagen as compared to calf type II collagen was found in the resistant strains. In six strains, resistance correlated with the expression of public Ia antigens cross-reactive with the public Ia antigens of BN. The non-MHC-linked BN genome also exerted a suppressive effect on the incidence and severity of CIA in strains carrying collagen-responder and CIA-susceptible RT1 alleles. Together, the data show that CIA in rats is under the control of multiple genes, both RT1-linked and nonlinked .