Abstract. We prepared pressure-sensitive adhesive (PSA) patches based on styrene-isoprene-styrene (SIS) thermoplastic elastomer using hot-melt coating method. The liquid paraffine is added in the PSA matrices as a plasticizer to moderate the PSA properties. Three drugs, methyl salicylate, capsaicin, and diphenhydramine hydrochloride are selected as model drugs. The Fourier transform infrared spectroscopy, differential scanning calorimetry test, and wide-angle X-ray diffraction test indicate a good compatibility between drugs and matrices. Peppas equation is used to describe drug release profile. Different drug-matrix absorption, as indicative of drug-matrix interaction, accounts for the variation in release profiles of different drugs. Furthermore, atomic force microscopy and rheological studies of the PSA samples are performed to investigate the effect of SIS structure and plasticizer of PSA on drug release behaviors. For methyl salicylate and capsaicin, drug diffusion in the PSA matrices is the main factor controlled by the release kinetic constant k. The high [SI] diblock content and high plasticizer amount in matrix provide the PSA with a homogeneous and soften microstructure, resulting in a high diffusion rate. But for water-soluble drugs such as diphenhydramine hydrochloride, the release rate is governed by water penetration with the competition from diffusion mechanisms.