Collagen-induced arthritis (CIA) is an experimental model in which a specific immune response to type II collagen (CII) is associated with the development of inflammatory arthritis. In this study, we evaluated the effects of early and delayed treatments with anti-Ia mAb and IFN-gamma on murine CIA. Administration of anti-Ia mAb at the time of immunization with CII decreased the incidence and delayed the onset of arthritis, whereas anti-Ia treatments begun 2 wk after immunization had no effect upon either arthritis incidence or onset. Neither treatment protocol resulted in a significant decrease in antibody titer or proliferative response to CII. Because IFN-gamma increases Ia expression in a variety of cells, we determined its effect on arthritis incidence and onset. When IFN-gamma treatments were begun at the time of immunization the incidence of arthritis was increased and arthritis onset was more rapid. Treatment with IFN-gamma did not result in an increase in anti-CII antibody levels. These results support the importance of Ia expression in the induction of murine collagen-induced arthritis, and suggest that suppression with anti-Ia antibodies and augmentation with IFN-gamma are not the result of changes in the humoral response to CII, but may be due to local effects within the target organ.