The interaction of activated CD44 with its ligand, low mw hyaluronan, is involved in inflammation, but no role has been identified for this interaction in the regulation of an immune response to infection. In these studies, infection of C57BL/6 mice with Toxoplasma gondii resulted in increased expression of CD44 on T cells, B cells, NK cells, and macrophages, and a small percentage of CD4+ T cells express an activated form of CD44. Administration of anti-CD44 to infected mice prevented the development of a CD4+ T cell-dependent, infection-induced inflammatory response in the small intestine characterized by the overproduction of IFN-γ. The protective effect of anti-CD44 treatment was associated with reduced production of IFN-γ, but not IL-12, in vivo and in vitro. Furthermore, the addition of low mw hyaluronan to cultures of splenocytes or purified CD4+ T cells from infected mice resulted in the production of high levels of IFN-γ, which was dependent on IL-12 and TCR stimulation. Together, these results identify a novel role for CD44 in the regulation of IFN-γ production by CD4+ T cells during infection and demonstrate a role for CD44 in the regulation of infection-induced immune pathology.