Enantiomeric separation of racemic mexiletine and fluoxetine was achieved using three chiral derivatizing reagents (CDRs) based on (S)-naproxen. Diastereomers were synthesized by reaction of mexiletine or fluoxetine with the CDRs and were separated on a C18 column under reversed-phase conditions using a binary mixture of acetonitrile and triethylammonium phosphate/water, with UV detection at 230 and 226 nm. The results obtained for enantioseparation of the two drugs using the three CDRs were compiled and compared. The conditions for derivatization and chromatographic separation were optimized. The method was validated for linearity, repeatability, limit of detection and limit of quantification.