As a novel separation mode of capillary electrophoresis (CE), liposome electrokinetic capillary chromatography (LEKC) has aroused considerable attention in recent years; however, the enantioseparation based on this new system has not been previously investigated. In this study, we proposed a brand-new LEKC chiral separation approach using liposomes comprised of phosphatidylcholine (PC) and cholesterol as pseudo-stationary phase and sulfobutyl ether-β-cyclodextrin (SBE-β-CD) as chiral selector. Compared with the single CD system and CD-SDS-MEKC system, this LEKC method presented an obviously preferable enantioseparation of four model drugs (naproxen, warfarin, ketoprofen and amlodipine). In this new established system, all the enantiomers represented baseline separations with the resolution and selectivity respectively achieving 1.584/1.067 (for naproxen), 2.226/1.045 (for warfarin), 1.537/1.038 (for ketoprofen) and 2.592/1.097 (for amlodipine), while other two comparative systems demonstrated no separation or a poor separation. Several important parameters affecting the enantioseparation, such as buffer pH, concentration of liposomes, phosphate buffer solution (PBS) and chiral selector (SBE-β-CD), and applied voltage were systematically investigated. Satisfactory repeatability was achieved through intra-day, inter-day and batch-to-batch investigations with relative standard deviations less than 3.40%. Furthermore, the established method was successfully applied to test the chiral impurity of naproxen sample.