Abstract The effect of cod-liver oil extract (CLOE) on the buccal permeation of ionized and nonionized forms of ergotamine (ERG) was investigated in vitro and compared with that of oleic acid which was a major component (ca. 16%) of CLOE. The apparent partition coefficient ( K) values of ERG were slightly increased upon the addition of enhancers, however, a significant difference was not observed between CLOE and oleic acid. To investigate the mode of action of CLOE, the permeability coefficients of the nonionized ( P n) and ionized forms ( P i) of ERG were determined in the presence and absence of enhancers. The P n values of ERG were markedly increased, especially CLOE; however, the P i values of ERG were almost constant upon the addition of each enhancer. It was clarified that CLOE mainly enhanced the permeation of the nonionized form of ERG.