A new capillary electrophoresis (CE) method was presented for the determination of asenapine, an atypical antipsychotic drug, in pharmaceuticals. Box-Behnken design, an experimental design method, was used to investigate the effects of run buffer pH, run buffer concentration and applied potential on the separation of asenapine and granisetron (IS). The optimum conditions were phosphate buffer (15 mM, pH: 3.1) with 25.7 kV voltage and 20 celcius capillary temperature. The method was validated according to ICH guideline. A good linearity was obtained in the concentration range of 0.27-6.4 mu g/mL with LOD and LOQ values of 0.07 and 0.24 mu g/mL, respectively. The precision and accuracy of the method were satisfying with intra and interday recovery values of 97.8-100.8% and RSD less than 2%. The proposed CE method was applied to asenapine tablets successfully, for the first time.