The effect of ethanol on the transport of organic ions in rabbit kidney cortical slices was studied. Ethanol at a concentration of 4 to 10% (v/v) reversibly inhibited the slice uptake of the organic anion, p-aminohippurate (PAH), in a dose-dependent manner, but had no significant effect on that of the organic cation, tetraethylammonium (TEA). Overall, the inhibitory effect on PAH uptake increased with the length of the hydrocarbon chain, with an I50 of 7.7, 0.9, and 0.05% for ethanol, butanol, and heptanol, respectively. The efflux of PAH was significantly decreased in the presence of 8% ethanol. Kinetic analysis indicated that ethanol decreased Vmax without a significant change in Km. Lowering the Na concentration in the incubation medium from 130 to 20 mM resulted in a disappearance of the above described inhibitory effect of ethanol on PAH uptake. Although Na-K-ATPase activity of renal cortical microsomes was significantly inhibited by ethanol (6-10%), butanol (1%), and heptanol (0.1%), there was no clear correlation between the effects of alcohols on PAH transport and/or Na-K-ATPase. Nevertheless, the results suggest that ethanol inhibits reversibly the Na-dependent transport of PAH from the medium into the cell across the basolateral membrane through a mechanism yet to be elucidated. The high degree of correlation between I50 and the partition coefficients of the alcohols suggested that their interaction with membrane lipids is important for the inhibition of PAH uptake, and also that PAH (but not TEA) transport is affected by alteration of the lipid environment of the membrane.