Cis-(Z)-flupentixol dihydrochloride (FLU), a thioxanthene drug, is used in therapy of schizophrenia as well as in anxiolytic and depressive disorders. Since the action mechanism of FLU is not completely understood, the main objective of present study is to provide a detailed evaluation of flupentixol-phospholipid membrane interactions at molecular level. FLU-dipalmitoylphosphatidylcholine (DPPC) interactions in presence and absence of cholesterol (CHO) were investigated as a function of temperature. The changes in upper part of membrane were more pronounced than those in central part of membrane, as indicated by EPR and FTIR. FLU was proposed to incorporate into phospholipid membranes with its triple ring parallel to head group and its chain toward alkyl chain of phospholipids. According to DSC results, the incorporation of 10 mol% FLU into DPPC caused a shoulder in transition peak, suggesting the occurence of a phase separation, and formation of this new phase is still observable in presence of CHO. It is well known that, structure and dynamics of lipids have significant influence on the function of membrane bound proteins, and consecutively their actions. Based upon these, it was proposed that FLU may modify membrane associated receptors and transport proteins, which would form the basis of its clinical efficiency. (C) 2016 Elsevier Ireland Ltd. All rights reserved.