Many lines of evidence support a close association between thyroid hormones and noradrenergic systems in peripheral tissues. However, there is little certainty regarding interactions of the two systems in brain. We now report that triiodothyronine is concentrated in both nuclei and projection sites of central noradrenergic systems. Immunohistochemical mapping of the hormone revealed the following: (1) Locus coeruleus and all other noradrenergic cell groups identified were the most prominently labeled neural centers in the brain. (2) The hormone was also concentrated in the widely dispersed targets of noradrenergic projections. (3) Triiodothyronine labeling in noradrenergic target cells was most prominent over the cell nuclei, indicating that the hormone was bound to its receptors. Therefore, targets of noradrenergic innervation should be responsive to triiodothyronine. (4) Unlike that in noradrenergic target cells, triiodothyronine staining was decidedly perikaryal in locus coeruleus (A-6) and the other A-1 to A-7 cell groups; the staining pattern in locus coeruleus cytosol and processes was heavy, clumped and similar to that seen in contiguous sections immunostained for tyrosine hydroxylase. Results of radio-immunoassay, immunoabsorption and pharmacological tests demonstrated the specificity of the antibody for triiodothyronine and ruled against cross-reactivity with norepinephrine or its metabolites as the basis for the staining reactions. Although other possibilities consistent with these new observations are given consideration, it appears that the structure and activity of central noradrenergic systems may be major determinants of triiodothyronine distribution patterns and actions in brain. If the noradrenergic system processes both triiodothyronine and norepinephrine and conducts them both to nerve cell groups receiving its terminal arborizations, specific postsynaptic receptors would be available for transduction of both sets of messages. The evidence provides a morphological basis for earlier proposals that triiodothyronine may play a neuromodulatory or neurotransmitter role in the adrenergic nervous system.