A rapid, sensitive and simple high performance liquid chromatographic method for the simultaneous determination of propafenone (PPF) and its metabolites (5-hydroxypropafenone, 5-OHP; N-depropylpropafenone, NDP) in serum has been developed. Separation of PPF, 5-OHP and NDP was achieved by reversed phase chromatography using a mobile phase consisting of 57% methanol and 43% 10 mmol/L potassium dibasic phosphate (pH 2.7) at a flow rate of 1.0 ml/min on a 5 microns ODS-C18 column. The eluent was monitored at 254 nm. The method showed a good linearity. The recoveries of PPF, 5-OHP and NDP were found to be 99.54 +/- 2.13%, 100.02 +/- 3.66% and 100.48 +/- 3.10%, respectively. Precision studies for both within day and day-to-day at different concentrations provided RSD values of less than 5%. Some commonly used drugs can be determined in the same procedure without interference except phenytoin. This method is well adapted to the therapeutic monitoring of PPF treated patients, as well as for pharmacokinetic studies.