Somatomedin C (SMC; insulin-like growth factor I) is thought to mediate the effects of growth hormone (GH) mainly on skeletal growth. SMC is produced in the liver but its production by various other fetal tissues including the brain, suggests a local regulatory role rather than a general one. A substance cross-reacting with recombinant human SMC (rSMC) was localized in the central nervous system (CNS) of the normal control and Snell dwarf mice by the unlabeled antibody peroxidase-antiperoxidase technique. rSMC-immunoreactive substance (rSMC-IRS) was found in the neuronal cells of forebrain structures. These included the caudate nucleus/putamen, hippocampus, thalamus, hypothalamus, globus pallidus and amygdala. No positive cells were found in the cerebral cortex. Investigation of the dwarf brain showed rSMC-IRS distributed in identical areas of the brain, although the intensity of the staining of rSMC-IRS was found to be weaker than that of the positive cells in the normal brain. Moreover, the number of positive cells was found to be less than in the normal brain. After treatment with bovine GH for 3 days the reduced number of positive cells and weaker staining in the cerebral sections of the dwarf mice did not change. Thus, rSMC may represent another peptide which is common to both the endocrine and the nervous system, with a potential neurotransmitter/neuromodulator function in the CNS.