The novel antidepressant mirtazapine enhances both noradrenergic and serotonergic neurotransmission. It is marketed as racemate and both enantiomers contribute to its pharmacological profile. Since cytochrome P450 (CYP2D6) is involved in the biotransformation of mirtazapine, a clinical study was carried out to investigate the importance of CYP2D6 for the in vivo disposition of mirtazapine. After administration of a single oral dose of racemic mirtazapine to extensive (EM) and poor metabolisers (PM) of debrisoquine there were no differences in the pharmacokinetic parameters of either the parent compound or demethyl metabolite using an achiral analysis. The analysis of the separate enantiomers, however, revealed differences in the disposition between EM and PM subjects. For the R-(-)-enantiomer there were no differences between EM and PM in any of the kinetic parameters. However, for S-(+)-mirtazapine the area under the plasma concentration-time curve was 79% larger in PM than in EM (p = 0.06) and a corresponding longer half-life was found (18.8 ± 4.7 and 13.2 ± 4.3 h, respectively; p = 0.04). It was, furthermore, found that the R-(-)-enantiomer was cleared preferably via N + -glucuronidation, whereas the S-(+)-enantiomer was cleared preferably via 8-hydroxylation, followed by conjugation with glucuronic acid. In vitro experiments showed that the hydroxylation step is catalysed mainly by the CYP2D6 isoenzym, and less extensively by the CYP1A2 isoenzym. It is therefore assumable that in subjects with deficiency of the CYP2D6 isoenzym, i.e. in PM subjects, hydroxylation may occur to a lesser extent. In line with this assumption metabolic plasma profiles showed in EM subjects relatively more 8-hydroxy glucuronide in comparison to the N + -glucuronide (ratio approx. 3.9), whereas in PM subjects relatively more N + -glucuronide was found in comparison to the 8-hydroxy glucuronide (ratio approx. 2.7). Nevertheless, the relatively higher plasma levels of the S-(+)-enantiomer in PM subjects are expected not to be of clinical importance, because both enantiomers are needed for the pharmacological action of mirtazapine.