Abstract This study deals with the relationship between the colloidal structure of a topical formulation and the drug release in vitro as well as the influence of the microstructure on the stratum corneum drug permeability. The nonsteroidal anti-inflammatory drug diclofenac diethylamine was chosen as model drug. The vehicles consist of phospholipids, diclofenac diethylamine and water. Depending on the ratio of the three components, these systems have various colloidal structures from liposomal dispersions via microemulsions to lamellar liquid crystals. The drug participates in the microstructure of the resulting systems. A dialysis membrane impregnated with silicone polymer was used for the in vitro release studies. The effective diffusion coefficient of diclofenac diethylamine changes rapidly with a phase transformation of the vehicle. Drug transport across the stratum corneum from aqueous solution and from vehicles with a high effective diffusion coefficient is controlled by the stratum corneum. In contrast to this observation the flux from the phospholipid drug systems with a low effective diffusion coefficient is controlled by drug release from the vehicle. The diffusional resistance inside these vehicles is higher than that in the stratum corneum. The drug release from liposomes is too slow, so that there is no stratum corneum permeation of diclofenac diethylamine from liposomes at all, either from large multilamellar vesicles or from small unilamellar vesicles. Fluoromicrography of cryosections of human skin shows that intact liposomes cannot penetrate deep into the skin. The fluorescence is limited to the cell layers of the stratum corneum.