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Nasal mucosa excised from dogs or rabbits was mounted as a flat sheet in an in vitro chamber. The permeability was assessed by measuring the unidirectional flux of the radiolabeled tracer compounds, water, sucrose, polyethylene glycol, and cholecystokinin octapeptide. The permeability coefficients calculated from the fluxes indicate that the nasal mucosa is moderately permeable to water-soluble compounds and compares with ileum or gallbladder. The addition of 0.5% sodium deoxycholate to the mucosal bathing solution caused a rapid, four- to fivefold increase in permeability to sucrose or cholecystokinin octapeptide. The increase in permeability was bidirectional, was not reversed by washing, and was accompanied by histological evidence of extensive loss of the surface epithelial layer. These results indicate that bile salts enhance nasal permeability by removing the epithelial cells, which constitute a major permeability barrier, rather than causing a chemical modification of the mucosal cells. This argues against the use of bile salts to enhance nasal drug absorption in patients.