We present a new and entirely mechanistic COSMOperm method to predict passive membrane permeabilities for neutral compounds, as well as anions and cations. The COSMOperm approach is based on compound-specific free energy profiles within a membrane of interest from COSMO-RS (conductor-like screening model for realistic solvation) calculations. These are combined with membrane layer-specific diffusion coefficients, for example, in the water phase, the polar head groups, and the alkyl tails of biochemical phospholipid bilayers. COSMO-RS utilizes first-principle quantum chemical structures and physically sound intermolecular interactions (electrostatic, hydrogen bond, and van der Waals). For this reason, it is unbiased toward different application scenarios, such as in cosmetics and industrial chemical or pharmaceutical industries. A fully predictive calculation of passive permeation through phospholipid bilayer membranes results in a performance of r2 = 0.92; rmsd = 0.90 log10 units for neutral compounds and anions, as compared to gold standard black lipid membrane experiments. It will be demonstrated that new membrane types can be generated by the related COSMOplex method and directly used for permeability studies by COSMOperm.