SJL mice spontaneously develop B cell lymphomas (historically described as reticulum cell sarcomas) by 12 months of age and inflammatory muscle disease (myositis) by 6 months of age. Tumors originate in mesenteric lymph nodes and in Peyer's patches and resemble human germinal center lymphomas. The growth of reticulum cell sarcomas is completely dependent on cytokine production by normal T cells. The spontaneous myositis, which resembles human idiopathic myositis, is characterized by various abnormalities in skeletal muscle, including infiltration with inflammatory cells consisting primarily of macrophages. The participation of different cytokines in the pathogenesis of the lymphoma and the massive invasion of macrophages into muscle tissues led us to investigate the possible involvement of nitric oxide (NO.), which is known to be synthesized by activated macrophages under inflammatory conditions. Elevated NO. production, measured by urinary nitrate excretion, by SJL mice in comparison with BALB/c control mice was observed as early as 7 weeks of age. Both aging and degree of spontaneous myositis correlated with increased nitric oxide production. Oral administration of N-monomethyl-L-arginine, an inhibitor of nitric oxide synthase (NOS), reduced urinary nitrate excretion and also the severity of myositis. Immunohistochemical analysis revealed the presence of inducible NOS (iNOS) in cells in the spleen, lymph nodes, and skeletal muscle. The iNOS is primarily responsible for the enhanced nitric oxide production. Morphology of cells that stained positive for iNOS was similar to that of macrophages infiltrating into the affected tissues. Chronic production of elevated amounts of nitric oxide by the SJL mice, therefore, provides a useful in vivo model for future studies of cellular damage resulting from endogenously produced NO.in combination with oxygen radicals.