Hyaluronanreceptor (CD44) has been shown to be involved in lymphocyte homing during normal leucocyte circulation and during leucocyte extravasation into sites of tissue inflammation. In addition, interaction with CD44 molecule induces T-cell activation and production of cytokines, such as interferon-γ. In this study we have examined what influence interaction with the CD44 receptor would have on collagen II-induced arthritis in mice. Mice were immunized with rat collagen II and administered with injections of a monoclonal anti-CD44 antibody. Seventeen days after the outbreak of the disease, all of the anti-CD44 treated animals remained clinically healthy, whereas 37% of the controls displayed arthritis (P<0.001). Ten days later the prevalence of arthritis was 26% and 65% (P<0.05), respectively. Furthermore, the severity of the arthritis was significantly ameliorated by the anti-CD44 treatment. Serum levels of interferon-γ were significantly higher in collagen II immunized animals having been treated with anti-CD44, compared to the controls. Delayed-type hypersensitivity (DTH) response was significantly decreased in the anti-CD44 treated animals, indicating a functional suppression of T cells. In contrast, T cell independent experimental inflammation was not affected by the administration of CD44 antibodies. Our results suggest that interaction with CD44 down-regulates T lymphocyte/monocyte mediated inflammatory reaction, possibly by triggering of interferon-γ release.