BACKGROUND The diversity of pharmacological actions of antidepressants suggests that they may bring about their clinical effects by different functional means. METHODS Twenty healthy volunteers were randomized in a cross-over design to receive 2 weeks of a clinical dose of both reboxetine and sertraline. Baseline assessments of personality were made using the Cloninger Tridimensional Personality Questionnaire and the Karolinska Scales of Personality. Daily and weekly ratings of mood (POMS and PANAS) and quality of life (SASS) were undertaken. RESULTS Reboxetine and sertraline differed in their effects on the SASS as well as on measures of mood. Reboxetine appeared more likely to be energy enhancing; the effects of sertraline were more difficult to quantify. Personality factors, such as harm avoidance predicted the preference of subjects for these effects and the effect of being on a preferred drug had a significant impact on SASS, and ratings of moods as well as on self-assessments of personality. CONCLUSIONS The differences reported here are consistent with the original thinking that led to the development of the SSRIs. The findings point to the need for further research on possible differential functional effects of psychotropic agents selective to different brain systems. The findings also have implications for clinical practice, in particular for maintenance treatment with antidepressants.