The presence of insulin-like growth factor-II (IGF-II) in brain and cerebral spinal fluid prompted us to investigate the distribution of receptors for this peptide in rat brain slices. Human 125I-IGF-II (10 pM) was incubated for 16 h at 4 degrees C with thaw-mounted slices of rat brain from 11 different brain regions. Incubations in the absence or presence of excess unlabeled human IGF-II or insulin were performed and the labeled tissues were exposed to X-ray film for 4-7 days. Autoradiographs showed dense labeling in the granule layers of the olfactory bulbs, deep layers of the cerebral cortex, pineal gland, anterior pituitary, hippocampus (CA1-CA4, and dentate gyrus), and the granule cell layers of the cerebellum. Unlabeled IGF-II eliminated most of the binding in these brain regions while insulin produced only a minimal reduction in the amount of 125I-IGF-II bound. These results indicate that a neural receptor for IGF-II is uniquely distributed in rat brain tissue supporting the notion that this peptide might play an important role in neuronal functioning.