Collagen-induced arthritis (CIA) developed in 70 to 90% of rats immunized with heterologous type II collagen. CIA was reduced to 0 to 18% when rats were injected i.v., i.e., pretreated, with 1 mg of soluble native type II collagen before immunization. Concomitant with the suppression of CIA were significant suppression of IgM, IgG, and delayed-type hypersensitivity (DTH) responses to type II collagen. Suppression of CIA and immunity to collagen was antigen-specific, related to dose and route of administration, and occurred only when 1 mg of collagen was injected i.v. either 32, 7, or 4 days before, or 7 days after immunization. Once CIA was established, however, neither arthritis nor immunity could be suppressed. To determine if adjuvant-induced arthritis (AIA), like CIA, could be suppressed by i.v. pretreatment with type II collagen, rats were given 1 mg of type II collagen or PBS i.v. before injection with mycobacteria and oil. AIA was not suppressed, and arthritis appeared in both groups at a similar incidence and severity. Sera from 26 rats with severe AIA that was collected between days 14 and 35 after injection were assayed for IgG to homologous rat type II collagen and were found to be negative. These findings further support the hypothesis that CIA in rats is mediated by immunity to type II collagen and also suggest that CIA and AIA have different primary pathogenic mechanisms.