Sodium salts of medium-chain fatty acids, sodium caprate (C10) in particular, have been used as absorption-enhancing agents to promote transmucosal drug absorption. In this study, we conducted both in vitro and in vivo experiments to investigate the effects of C10 on intestinal permeabilities and mucosal morphology. Mucosal addition of C10 (13-25 mM) reduced the transepithelial electric resistance (TEER) of cultured monolayers of the human intestinal cell line Caco-2 by 40-65% and, upon removal of C10, a marked tendency of TEER recovery was recorded. C10 added mucosally at 13-50 mM increased the transports of mannitol and polyethylene glycol (PEG) 900 across Caco-2 in a dose-dependent manner. In contrast, the transport of a model D-decapeptide was maximally enhanced with 20-25 mM C10. No noticeable morphological alteration of the Caco-2 monolayers was observed after a 1-h mucosal pretreatment with C10. Co-delivery with C10 (0.05-0.5 mmol/kg) into the rat terminal ileum increased the D-decapeptide bioavailability (BA) dose-dependently. With 0.5 mmol/kg C10 co-administered, D-decapeptide percent BA was elevated from 2 to 11%. Following a 1-h incubation with 0.5 mmol/kg C10 (in liquid or powder form) non-invasively delivered into the rectal lumen, no signs of histological change in the rectal mucosa were detected. These results demonstrate that C10 can promote intestinal absorption of a small peptide without causing detrimental alterations of the intestinal mucosa. C10 thus seems to be a good candidate as an enhancing agent for improving the oral BA of small therapeutic peptides.