Theoretical analysis of the permeation process in percutaneous absorption is important for the molecular design of bioavailable transdermal drugs. In the present study, we examined the difference in permeability of nitrophenols across newborn rat abdominal skin and analyzed the structure-permeability correlation by molecular orbital calculation. The permeable rate of o-, n-, p-nitrophenol and 2,4-, 2,5-, 2,6-dinitrophenols was 0.291, 0.212, 0.085 and 0.042, 0.109, 0.027 micromol/cm2/h, respectively. The permeability of the nitrophenols correlated with their pKa values, indicating the ionizing process related to the permeation through the skin. The pKa values better correlated with the ionization potential (IP) energies than lowest unoccupied molecular orbital (LUMO) energies. Solvation free energies (dGW) of molecular form nitrophenols correlated better with permeabilities (pA) than partition coefficients (log P). In analyzing the dGW values with the permeability at pH 7.4, o-nitrophenol outlay from the theoretical line by ortho-effect. We conclude solvation free energy is a practical parameter and very useful for the molecular design of transdermal drugs.