1 Therapeutic serum concentrations of ethosuximide, phenobarbitone, primidone, and dipheylhydantoin were assayed from 1 ml of human serum. The extraction procedure was common to all four drugs and three internal standards. 2 Subsequent isothermal gas chromatographic analysis of serum extracts produced well resolved peaks for the underivatized quantitation of ethosuximide and phenobarbitone. Primidone and diphenylhydantoin were determined as methylated derivatives. 3 Mean coefficients of variation for the assay of each drug were less 7% on a newly packed and conditioned column and less than 10% after the technique had been in continuous use for 3 months. 4 The advantage of quantitation relative to peak area ratios rather than peak height ratios was minimal for the determination of ethosuximide, primidone and diphenylhydantoin but appeared significant for the assay of phenobarbitone.