The effects of two contra‐ions, namely benzoate (Bz) and oleate (Ol), on the in vitro human skin permeability of propranolol racemate (RS‐PR) or S‐enantiomer (S‐PR) were studied. Saline solution (SS) or mineral oil (MO) were selected as vehicles. The MO increased the permeability coefficient (Kp) of PR‐Bz (pKp ≈ 4) of about four times with respect to SS (pKp ≈ 8) probably due to the ion pair formation. The steady‐state flux of S‐enantiomers resulted about twofold higher than that of racemates according to their lower melting temperatures with the exception of (S)‐PR‐Ol and (RS)‐PR‐Ol vehicled in SS which not resulted statistically different. This anomalous result could be explained considering the behavior of (RS)‐PR‐Ol or (S)‐PR‐Ol in aqueous solutions: these salts formed ion pairs which associated to form aggregates up to a concentration of 20 µg/mL as verified by light scattering. Therefore, their effective concentrations in SS resulted similar and justified the overlapped skin permeation profiles. All three considered variables, namely counterion, vehicle, and chirality, resulted mutually interfering on and deeply influenced the passive diffusion process of PR. © 2009 Wiley‐Liss, Inc. and the American Pharmacists Association J Pharm Sci 99: 1217–1224, 2010