The presence of inducible nitric oxide synthase (iNOS) in fresh monocytes from patients with Graves' disease was demonstrated for the first time. Immunophenotypic analysis showed a profile reflecting a state of activation and differentiation of monocytes. Incubation of lymphomononuclear cells from healthy volunteers in the presence of synthetic peptides with sequences related to thyroid autoantigens (TSH receptor, thyroid peroxidase, or thyroglobulin) led to a stimulation of monocytes manifested by a change in phenotype and expression of iNOS. This expression did not take place on isolated monocytes, unless products associated with Th1 activity were present in the medium. Active peptides contained a characteristic "2-6-11" motif already described [López-Moratalla et al. (1995) Biochim. Biophys. Acta 1265, 181-188]. These results are suggestive of a new role for autoantigens in the pathogenesis of Graves' disease: that of inducing the expression of iNOS and activating the monocyte possibly underlying the autoimmune response.