In this communication, we demonstrate that adult mammalian brain neurons express transforming growth factor-α (TGF-α). We used the anti-TGF-α monoclonal antibody, MF9, to immunohistochemically localize TGF-α in human and rat brain. We found specific immunoreactivity in neurons throughout the brain which was not a result of cross-reactivity of MF9 with the neuropeptide, synenkephalin. Northern blot analysis of bovine and rat brain RNA using human and rat TGF-α cDNA probes, respectively, revealed a single 4.8-kilobase pair mRNA with approximately equal abundance in the bovine brainstem, cerebellum, hypothalamus, and cerebral cortex. Fetal rat brain had about 2-fold more TGF-α mRNA than did adult rat. The brain TGF-α cDNA was cloned from a human neonatal brainstem library. Four identical clones were isolated after screening 106 recombinant λgt11 phage. The sequence of the 894-base pair cDNA was virtually identical with the cDNA isolated from a human renal cell carcinoma. A single alanine codon was deleted in the brain cDNA at an exon-exon junction. The alanine deletion is within the amino-terminal region of the TGF-α precursor that is thought to be removed by proteolytic processing of the precursor to the mature growth factor. These studies indicate that the normal mammalian brain neurons express TGF-α.