A B S T R A C T The permeability coefficients of a homologous series of amides from formamide through valeramide have been measured in spherical bilayers prepared by the method described by Jung. They do not depend directly on the water:ether partition coefficient which increases regularly with chain length. Instead there is a minimum at acetamide. This has been ascribed to the effect of steric hindrance on diffusion within the bilayer which increases with solute molar volume. This factor is of the same magnitude, though opposite in sign to the effect of lipid solubility, thus accounting for the minimum. The resistance to passage across the interface has been compared to the resistance to diffusion within the membrane. As the solute chain length increases the interface resistance becomes more important, until for valeramide it comprises about 90% of the total resistance. Interface resistance is also important in urea permeation, causing urea to permeate much more slowly than an amide of comparable size, after allowance is made for the difference in the water:ether partition coefficient. Amide permeation coefficients have been compared with relative liposome permeation data measured by the rate of liposome swelling. The ratios of the two measures of permeation vary between 3 and 16 for the homologous amides~ The apparent enthaipy of liposome permeation has been measured and found to be in the neighborhood of 12 kcal mo1-1 essentially independent of chain length. Comparison of the bilayer permeability coefficients with those of red cells shows that red cell permeation by the lipophilic solutes resembles that of the bilayers, whereas permeation by the hydrophilic solutes differs significantly.Nonelectrolyte diffusion across the red cell membrane provides information about membrane physical characteristics (1), which has been interpreted in the light of comparisons with model lipid bilayer systems such as liposomes (2). The multilamellar structure of the liposomes makes it difficult to obtain absolute permeability coefficients from the initial rate of swelling, the usual measure of liposome permeation. However, absolute permeability coefficients can be obtained from measurements of diffusion across bilayers. Though Andreoli et al. (3) report that the permeability coefficients of small nonelectrolytes are generally too small to measure across planar bilayers, such measurements have been made by Vreeman (4), Gallucci et al. (5,6), Lippe et al. (7,8), and Jung (9). We have used spherical lipid bilayers, prepared by the method of Jung (9), to obtain permeability coefficients across single spherical bilayers for a homologous series of monoamides and urea. These permeability coefficients are qualitatively,