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Graphical abstract Abstract Cholesterol (Chol) is one of the major skin barrier lipids. The physiological level of Chol in the stratum corneum (SC) appears to exceed its miscibility with other barrier lipids, as some Chol is phase separated. Chol synthesis is essential for epidermal homeostasis, yet the role of these Chol domains in SC permeability is unknown. We investigated the impact of Chol depletion on the permeability properties and microstructure of model membranes and human SC. X-ray powder diffraction of membranes constructed from isolated human skin ceramides or synthetic ceramides confirmed that only approximately half of the normal Chol amount can be incorporated in either long or short periodicity lamellar phases. The long periodicity lipid arrangement persisted even in the absence of Chol. Infrared spectroscopy suggested that Chol had negligible effects on the lipid chain order and packing at physiological skin temperature. Chol depletion of the model membranes or isolated human SC did not compromise the barrier function to water and two model permeants. On the contrary, the membrane with the Chol content reduced to 40% of the normal value, where no separated Chol was observed, was significantly less permeable than the control. Thus, a 0.4:1:1 M ratio of Chol/ceramides/fatty acids appears sufficient for skin lipids to limit water loss and prevent the entry of environmental substances. We speculate that the SC Chol domains may have roles in the skin other than barrier function. [ABSTRACT FROM AUTHOR]