A new method was developed for the quantitative analysis of chlorpheniramine in serum using the high sensitivity and selectivity of GLC-mass spectrometry with selected-ion monitoring. Intense fragment ions at m/e 203 and 207 from the drug and a tetradeuterated analog, respectively, are monitored continuously. The deuterated quantitation standard can be prepared by a simple exchange reaction. A linear calibration curve was obtained over the range of 0-160 ng/ml of serum using 85 ng of the standard/ml. The sensitivity limit is 1-2 ng/ml, and each serum extract can be analyzed in less than 2 min. The method was applied to a measure chlorpheniramine concentrations through at least 1.5 biological half-lives.