Insulin receptor-related receptor (IRR) is a member of the insulin receptor family. However, its endogenous ligand and physiological roles are unknown. To elucidate the physiological roles of IRR, an orphan receptor, in the brain, we examined its expression at mRNA and protein levels in the brain by in situ hybridization and immunohistochemistry, respectively. The expression of IRR mRNA in the brain was highly restricted to the forebrain including the nucleus of the diagonal band, medial septal nucleus, ventral pallidum, accumbens nucleus and caudate putamen, and the brainstem including the prepositus hypoglossal nucleus, medial vestibular nucleus, gigantocell reticular nucleus, paragigantocellular nucleus and ventral cochlear nucleus. Most IRR mRNA-positive cells in the forebrain but not in the brainstem were cholinergic neurons. However, most IRR mRNA in the forebrain and brainstem was coexpressed with that of trkA, a high-affinity receptor for nerve growth factor. IRR-immunoreactive cell bodies were also detected in the forebrain and brainstem. The pattern of IRR immunoreactivity was similar to that of IRR mRNA. Its restricted pattern indicates that IRR plays unique roles in the brain, in contrast to insulin and insulin-like growth factor-I receptors, other members of the insulin receptor family, which are widely expressed in the brain.