A new method for measuring zonisamide (ZNS) in plasma by high-performance liquid chromatography was developed by using a 2-microm reversed-phase non-porous silica column. ZNS in plasma was first purified with a column extraction technique and injected onto the non-porous silica column. Calibration curve was linear over the concentration range of 1-80 microg/ml in plasma. The recoveries of ZNS added to plasma were more than 95.4% with the coefficient of variation less than 9.0%. We developed a rapid routine method using the non-porous silica column that was accurate and improved solvent consumption in the measurement of ZNS.