Decreasing brain 5-HT levels by acute tryptophan depletion has been shown to selectively impair cognition in healthy volunteers. In bipolar disorder, ATD causes measurable neurophysiological effects without altering mood. The purpose of this study was to examine the effects of ATD on neuropsychological performance in 14 euthymic bipolar patients. Cognitive function was evaluated 4-6 h after ingestion of a control or depleting amino-acid drink. Plasma tryptophan levels fell significantly following the depleting drink, however there were no main effects on the ID/ED set-shift task, Paired Associates Learning or Vigil. A trend towards a decrease in the proportion of perfect solutions on the Tower of London task was observed when depleted. While ATD reduces 5-HT levels in the brain, it does not appear to alter neuropsychological performance on tests of sustained attention or associative learning. Effects on specific 'executive' functions are less clear, and should be the focus for future research.