The extent and clinical significance of the pharmacokinetic interaction between fluoxetine and haloperidol was studied in 13 schizophrenic patients with prominent negative symptoms. Patients stabilized on chronic low-dose haloperidol (3-8 mg day-1) received additional fluoxetine (20 mg day-1) for 12 consecutive weeks. Mean plasma concentrations of haloperidol increased significantly from 6.5 +/- 2.4 nmol l-1 at baseline to 8.8 +/- 3.6 nmol l-1 (P < 0.01) at week 12 of fluoxetine treatment, but this effect was not associated with an increase in mean extrapyramidal side effects score on the Simpson and Angus Scale. The improvement in negative symptomatology, as measured by the Scale for Assessment of Negative Symptoms, did not correlate significantly with the increase in plasma haloperidol levels. Though our findings confirm that fluoxetine impairs haloperidol clearance, this interaction is unlikely to have adverse clinical consequences, at least in patients chronically stabilized on a low dosage of haloperidol. As fluoxetine is a potent inhibitor of cytochrome P450 (CYP) 2D6, these results also provide indirect evidence for an involvement of CYP2D6 in the metabolism of haloperidol.