A method for the simultaneous determination of the three selective serotonin reuptake inhibitors (SSRIs) citalopram, fluoxetine, paroxetine and their metabolites in whole blood and plasma was developed. Sample clean-up and separation were achieved using a solid-phase extraction method with C8 non-endcapped columns followed by reversed-phase high-performance liquid chromatography with fluorescence and ultraviolet detection. The robustness of the solid-phase extraction method was tested for citalopram, fluoxetine, paroxetine, Cl-citalopram and the internal standard, protriptyline, using a fractional factorial design with nine factors at two levels. The fractional factorial design showed two significant effects for paroxetine in whole blood. The robustness testing for citalopram, fluoxetine, Cl-citalopram and the internal standard revealed no significant main effects in whole blood and plasma. The optimization and the robustness of the high-performance liquid chromatographic separation were investigated with regard to pH and relative amount of acetonitrile in the mobile phase by a central composite design circumscribed. No alteration in the elution order and no significant change in resolution for a deviation of +/-1% acetonitrile and +/-0.3 pH units from the specified conditions were observed. The method was validated for the concentration range 0.050-5.0 micromol/l with fluorescence detection and 0.12-5.0 micromol/l with ultraviolet detection. The limits of quantitation were 0.025 micromol/l for citalopram and paroxetine, 0.050 micromol/l for desmethyl citalopram, di-desmethyl citalopram and citalopram-N-oxide, 0.12 micromol/l for the paroxetine metabolites by fluorescence detection, and 0.10 micromol/l for fluoxetine and norfluoxetine by ultraviolet detection. Relative standard deviations for the within-day and between-day precision were in the ranges 1.4-10.6% and 3.1-20.3%, respectively. Recoveries were in the 63-114% range for citalopram, fluoxetine and paroxetine, and in the 38-95% range for the metabolites. The method has been used for the analysis of whole blood and plasma samples from SSRI-exposed patients and forensic cases.