The current study was carried out to investigate the cognitive effects of two serotonin reuptake inhibitors (SSRIs), sertraline and paroxetine, with special reference to differences in their affinity for other neurotransmitter systems, i.e. anticholinergic activity of paroxetine and putative dopamine reuptake activity of sertraline. The study was conducted according to a double-blind, three-way cross-over design. During three treatment periods of 2 weeks, 24 healthy middle-aged (aged 30-50 years) subjects of both sexes received sertraline (50 mg on days 1-7, 100 mg on days 8-14), paroxetine (20 mg on days 1-7, 40 mg on days 8-14) and placebo. Paroxetine specifically impaired delayed recall in a word learning test at a dose of 20 and 40 mg. Sertraline did not affect word learning but improved performance on a verbal fluency task at a dose of 50 and 100 mg. Neither drug affected performance on a short-term memory scanning task. These subtle but significant changes in cognitive performance can be explained by subtle differences in pharmacological profiles of these SSRIs. The additional anticholinergic effects of paroxetine could account for its induction of long-term memory impairment. Similarly, the additional dopaminergic effects of sertraline could account for its induction of slightly improved verbal fluency. The impairing and facilitating cognitive effects of paroxetine and sertraline, respectively, may be more pronounced in the elderly depressed patient.