A novel CE method was successfully applied to the enantioseparation of pantoprazole and related benzimidazoles, such as tenatoprazole, lansoprazole, and omeprazole. The chiral resolution was performed in an untreated fused-sillica capillary using a dual chiral selector system consisting of copper (II)-l-histidine (l-His) complex and hydroxypropyl--CD. The primary factors affecting its separation efficiency, such as chiral selector, buffer pH, and applied voltage, were optimized. The best results were obtained by using a buffer consisting of 20mg/mL hydroxypropyl--CD, 10mmol/L copper(II) acetate, 15mmol/L l-histidine, 5.0mmol/L phosphate adjusted to pH5.0, and 15kV applied voltage. The enantiomers of all compounds were fully resolved within 20min with high resolutions of 3.9 to 6.2. The optimized method was extensively validated for determination of the R-(+)-enantiomer impurity in S-(-)-pantoprazole. The LOD and LOQ for the R-(+)-enantiomer were 1.0 and 2.5g/mL, respectively. A good linear relationship was obtained in the concentration range of 2.5-25g/mL with r(2)0.999 for the R-(+)-enantiomer. The percentage recovery of the R-(+)-enantiomer ranged from 91.6 to 101.3. The method is capable of determining a minimum limit of 0.1% w/w of R-(+)-enantiomer in S-(-)-pantoprazole bulk samples.