We investigated the effect of gamma-interferon (gamma-IFN) on the development of type II collagen (CII)-induced arthritis. DBA/1 mice were immunized with rat CII and 16 days later, were treated with subcutaneous injections of recombinant rat gamma-IFN into the right paws twice a week. Compared with controls, the gamma-IFN-treated mice developed arthritis with a higher frequency and severity. Immunohistochemical analysis of gamma-IFN-treated paws from CII-immunized mice revealed an increase in the numbers of class II antigen-expressing cells and an infiltration of CD4+ lymphocyte-like cells. The auto-antibody response toward CII was suppressed by gamma-IFN treatment. The findings implicate gamma-IFN in a role that triggers arthritis by enhancing local inflammatory processes in the joints, or possibly, by permitting homing of T cells to the joints.