Conflicting reports have led to the description of nitric oxide as a "double-edged sword" in animal models of autoimmunity. In this study we show that tissue damage within the eye during experimental autoimmune uveoretinitis correlates with peroxynitrite formation in infiltrating monocytes/macrophages within the outer retina together with extensive photoreceptor apoptosis and apoptosis of Fas(+) T cells within the retina. Inducible nitric oxide synthase (NOS2) expression was primarily restricted to infiltrating monocytes/macrophages in the outer retina and photoreceptor rod outer segments (target tissue), but despite showing evidence of lipid peroxidation, myeloid cells remained resistant to apoptosis. The protective effect of the NOS inhibitor N(G)-nitro-L-arginine methyl ester could be attributed to dramatically reduced photoreceptor apoptosis, absence of nitrotyrosine formation, and reduced NOS2 protein expression. However, inhibition of NOS by N(G)-nitro-L-arginine methyl ester was accompanied by a sparing of CD3(+) and CD2(+) T cells despite continued expression of Fas and Fas ligand, thus compromising functional inactivation of T cells in the target tissue. These data suggests that in addition to contributing to tissue damage in the retina through generation of reactive oxygen species, nitric oxide also seems to be required for activation-induced cell death and elimination of T cells in the retina.