A robust and rapid high-performance liquid chromatography (HPLC) method is described for therapeutic drug monitoring of fluoxetine and norfluoxetine in the presence of six frequently-used tricyclic antidepressants and their respective metabolites. Liquid-liquid extraction into n-hexane/acetonitrile is used with reextraction into hydrochloric acid for clean-up. The chromatographic separation is carried out on a CN column. The minimum detectable amount is 3 ng injected on column. In addition to qualitative and quantitative validation data for the assay method, results from patient samples are presented. It is concluded that for patients treated with fluoxetine, therapeutic drug monitoring is valuable for optimizing the therapy.