Interferon‐γ (IFN‐γ) exerts both enhancing and suppressing influences on collagen‐induced arthritis (CIA), depending on the route and protocol of administration. To study the role of IFN‐γ on the autoimmune process of CIA, we treated DBA/1 mice with two different rat monoclonal antibodies (mAb) to murine IFN‐γ. Treatments, given twice weekly for 4 weeks, consisted of intraperitoneal injections of either mAb. In early treatments, starting from the day of immunization with type II collagen (CII), the severity of arthritis was reduced in both groups of anti‐IFN‐γ‐treated mice compared with control groups. Moreover, anti‐CII antibody levels decreased in the sera of these mice. CIA was also down‐regulated in mice treated from days 14 or 28 post immunization. In contrast, late treatments with anti‐IFN‐γ mAb either induced aggravating effects, or did not affect the course of the disease. On the other hand, administration of high doses (8 × 10⁴ U three times/week) of rat recombinant IFN‐γ exerted a transient increase of CIA severity. These findings suggest that IFN‐γ may play a critical role during both the induction and the course of CIA, first enhancing the immune response, and then regulating the arthritis process.