Purpose. Investigation of the relationship between changes in human SC lipid organization induced by N-alkyl-azocycloheptane-2-one and SC permeability to the model compound HgCl2. Methods. Human dermatomed skin was treated with propylene glycol (PG), oleyl-Azone (OAz) or dodecyl-Azone (DAz) in 0.15 M PG. Untreated skin served as control. The lateral lipid organization was studied by electron diffraction. Hg was measured on tape-strips by X-ray microanalysis and in the acceptor phase by atom absorption spectrometry. Results. In control and PG treated samples, the lipid packing was mainly orthorhombic, while a small fraction was hexagonal. In OAz and DAz treated samples, the orthorhombic lipid organization remained, however, the hexagonal packing was recorded less frequently. The amount of Hg decreased as a function of depth in all SC samples, however, the penetration profile increased significantly upon OAz treatment. The cumulative amount of Hg in the acceptor phase of OAz treated samples also increased significantly compared to control and PG treated samples. Conclusions. The increased penetration of Hg into OAz treated skin could not be related to an orthorhombic-hexagonal phase transition. Alternatively, phase separation of OAz and/or formation of grain boundaries might affect SC permeability, hereby increasing Hg penetration. A similar mechanism is proposed for DAz.