Cyclo(His-Pro) (cHP) is an endogenous, enzymatically resistant, biologically active peptide. We examined its ability to be absorbed after oral administration. cHP radioactively labeled with 125I (I-cHP) was fed to adult mice, and blood and tissue samples were taken 15-90 min later. Radioactivity quickly appeared in blood at levels about one half to one fourth those previously found after IV injection. The highest concentrations were in the kidney and liver, but the testes, muscle, lung, and brain also contained more radioactivity than was accounted for by their vascular spaces. Between 25-32% of the radioactivity recovered from blood 30 min after feeding eluted on high-performance liquid chromatography in the position of intact peptide. Oral cHP reversed ethanol-induced narcosis, an effect previously found to occur within the brain. These results show that cHP can be absorbed orally in amounts sufficient to affect the CNS.