Background: As depression is a considerable risk factor for an unfa- University of Maastricht, The Netherlands vourable course of myocardial infarction (MI), antidepressant treatment of post-MI depression and, inherent to MI status, polypharmacy has become an important issue. Objective: The present study is the first to evaluate cognitive side effects of fluoxetine, as part of a placebo-controlled double-blind trial, in patients with post-first MI depression. Methods: Cognitive performance of 54 depressed patients post first-MI treated with fluoxetine or placebo was compared. Cognitive performance was tested before and after 9 weeks of treatment using the Visual Verbal Learning Test, Concept Shifting Task, Stroop Colour-Word Test and Letter-Digit-Substitution Test. Results: The median number of cardiovascular drugs taken by MI patients was 4.9. There were no differences between the fluoxetine and the placebo group on cognitive performance. Conclusion: In sum, there were no negative side effects of fluoxetine compared with placebo on cognition in depressed MI patients, simultaneously treated with cardiac drugs.