A method for routine therapeutic monitoring of serum tricyclic antidepressants (TCA) which offered good reproducibility, detection limits, linearity and specificity and which was simple, rapid and inexpensive to perform was developed. The method described uses Clin-Elut columns to facilitate the extraction. The analysis is by high pressure liquid chromatography (HPLC) with a CN bonded phase column, a mobile phase of acetonitrile/pH 7.0 phosphate/methanol and detection at 210 nm. This chromatographic system gives short equilibration times, stable calibration curves, high sensitivity and resolution, short retention times and long column life. The method is useful for determination of amitriptyline, doxepine, imipramine, nortriptyline, nordoxepin, desipramine and protriptyline. Trimipramine is used as an internal standard for the tertiary amines and protriptyline for the secondary amines. Recovery is linear from 25-1000 ng/ml. Rubber stoppers of a new formulation in Vacutainer blood collection tubes do not affect serum TCA levels. Sera from 53 psychiatric patients suffering from endogenous depression were analyzed using the procedure presented. The mean serum level of 4 patients on amitriptyline therapy having complete remission was 201 ng/ml (range, 123-259). The mean serum level of 4 patients on imipramine therapy rated as having complete remission was 200 ng/ml (range, 145-258). These values compare with recently published therapeutic ranges.