Two chromatographic methods, high-performance liquid chromatography (HPLC) and high-performance thin-layer chromatography (HPTLC) were compared for sensitivity and reproducibility in the analysis of the tricyclic antidepressant doxepin and its metabolite, desmethyldoxepin, in plasma. The HPLC procedure yielded a better reproducibility, as reflected by the coefficient of variation, and a higher sensitivity, as reflected by the minimum detectable quantity. The application of these methods for therapeutic and subtherapeutic monitoring of plasma levels of the drug is described.