To support the pharmacokinetic and bioavailability study of an extended-release loratadine (LOR)/pseudoephedrine sulfate (PES) tablet, a high performance liquid chromatographic-electrospray ionisation-mass spectrometric method (LC-MS) was developed for the simultaneous determination of LOR and PES in human plasma. Diazepam (DP) and phenylpropanolamine (PPA) were used as internal standards for LOR and PES, respectively. Analytes were extracted from alkalized human plasma by liquid/liquid extraction using ethyl ether. Chromatographic separation was performed on an ODS column at flow rate of 0.2 ml/min. The total chromatographic run time was 10.5 min with the retention time of 7.1 min and 6.2 min for LOR and DP, respectively, and 2.2 min for both of PES and PPA. The LOQ was 10 pg/ml and 50 pg/ml for LOR and PES, respectively. The method is accurate and precise enough for its intended purpose.