Erythromycin (ERY) is used in the topical treatment of acne vulgaris. In order to decrease the amount of microorganisms markedly, the antibiotic must penetrate into the sebaceous follicles. Firstly, the aim of this study was to improve the lipophilicity of ERY by ion pairing. Secondly, a formulation with optimized penetration of the ion pair was developed. Thirdly, the optimized formulation was compared with formulations containing ethanol and with the commercial product Zineryt. The determination of lipophilicity was based on partition coefficients (PC) and on the penetration of ERY into a modified multilayer membrane system (MMS). It was shown that the penetration of ERY into a lipophilic acceptor system was three times higher when ion pairing between ERY and octadecansulfonate was used in comparison with the penetration of the ERY base alone. The dosage of the antibiotic used can be markedly reduced by optimizing a vehicle for the ion pair.