Based on the blend of styrene-isoprene-styrene (SIS) thermoplastic elastomer and acrylic resin Eudragit 庐; EPO, amphiphilic hot-melt pressure sensitive adhesives (HMPSAs) were fabricated. Compatibility and micromorphology of SIS/EPO blends (SEBs) were analyzed with differential scanning calorimetry (DSC), atomic force microscopy (AFM) and scanning electron microscopy (SEM). The results showed that when the mass ratio of SIS to EPO was 1:1~1:2, bicontinuous structure was formed. Following the addition of an appropriate amount of polyethylene glycol (PEG), mineral oil and C 5 resin, the amphiphilic HMPSAs were prepared. Because of the compatibility between SIS and EPO, as well as the hydrogen bond interaction between EPO and PEG, amphiphilic HMPSAs showed good thermostability. The adhesive performance of HMPSAs was measured with 180掳 peeling strength and holding power. Geniposide and oleanolic acid were used as model drugs to investigate drug release behavior. When the mass ratio of PEG to SEB was 13:30~16:30, the HMPSAs could maintain good adhesion performance and achieve continual release of both hydrophilic and lipophilic drugs. In weakly acidic conditions, the HMPSAs exhibited good hygroscopicity and release profile, it was shown that pH sensitive amphiphilic HMPSAs were more suitable for transdermal drug delivery system (TDDS).