A high-performance liquid chromatographic method has been developed for the determination in human plasma of the specific serotonin reuptake inhibitor (SSRI) antidepressant paroxetine and its three main metabolites (M1, M2, M3). Fluorescence detection was used, exciting at lambda = 294 nm and monitoring emission at lambda = 330 nm for paroxetine (lambda(exc) = 280 nm, lambda(em) = 330 nm for M1 and M2; lambda(exc) = 268 nm, lambda(em) = 290 nm for M3). Separation was obtained on a reversed-phase C18 column using a mobile phase composed of 66.7% aqueous phosphate at pH 2.5 and 33.3% acetonitrile. Imipramine (lambda(exc) = 252 nm, lambda(em) = 390 nm) was used as the internal standard. A careful pre-treatment of plasma samples was developed, using solid-phase extraction with C8 cartridges (50 mg, 1 mL). The calibration curves were linear over a working range of 2.5-100 ng mL(-1) for paroxetine and of 5-100 ng mL(-1) for all metabolites. The limit of detection (LOD) was 1.2 ng mL(-1) for PRX and 2.0 ng mL(-1) for the metabolites. The method was applied with success to plasma samples from depressed patients undergoing treatment with paroxetine. Hence, the method seems to be suitable for the therapeutic drug monitoring of paroxetine and its main metabolites in depressed patients' plasma.