The novel drug zimelidine 50–300 mg/day was administered to 12 depressed patients. After about 3 weeks plasma levels of the demethyl metabolite, norzimelidine, were almost thrice those of the parent drug. During incubation of slices of rat brain cortex in plasma from the treated patients, the neuronal uptake of serotonin and noradrenaline was 51.7±10.2 and 82.8±9.6%, respectively, of the control values. The uptake inhibition both of serotonin and noradrenaline was correlated with the plasma level of norzimelidine (r=0.62 and 0.63, respectively). The major central metabolites of serotonin (5-HIAA) and noradrenaline (HMPG) in cerebrospinal fluid (CSF) decreased significantly (29 and 11%, respectively) during treatment with zimelidine. Although there was no mean change in the major dopamine metabolite (HVA) in CSF, the level during treatment (as percentage of the pretreatment level) was correlated with the effect on 5-HIAA in CSF. Thus, administration of zimelidine caused a relatively selective inhibition of serotonin uptake, mainly due to norzimelidine. A small but significant inhibition of noradrenaline uptake was also seen, but this effect was less pronounced than during chlorimipramine treatment. There was also an effect on the dopaminergic system, probably secondary to the action on serotonergic neurons.