A rapid, precise, and sensitive method has been developed for the simultaneous determination of five antiepileptic drugs (carbamazepine, phenobarbital, diphenylhydantoin, primidone, and oxcarbazepine) and six metabolites (from carbamazepine, carbamazepin-10,11-epoxide; from phenobarbital, p-hydroxyphenobarbital; from primidone, 2-phenyl-2-ethylmalonamide; from diphenylhydantoin, 5-(p-hydroxyphenyl)-5-phenylhydantoin) in human serum. Separation was achieved by means of liquid chromatography with a diode array detector (DAD) using reverse-phase ODS-Hypersil columns (100 Â 2.1 mm) with particle size of 5 mm, flow-rate 0.6 mL/minute, column temperature 408C, wavelength: 210 nm. Mobile phase was a gradient consisting of solvent A: phosphate buffer pH 5.7, solvent B: MeOH. Two procedures were tested for the serum treatment: protein precipitation with acetonitrile and solid-phase extraction with C 18 cartridges. The best recoveries were found by means of protein precipitation. Solid-phase extraction gave poor recoveries for phenobarbital and its metabolite. The results obtained are suitable in terms of precision, linearity, and accuracy for the simultaneous determination of serum levels of the mentioned drugs in the usual therapeutic ranges.