Objective: The purpose of this study was to determine whether vagus nerve stimulation influences cognitive flexibility and creativity. Methods: Ten subjects, in whom vagus nerve stimulators had been implanted for the treatment of intractable seizures, performed tasks that assessed cognitive flexibility (solving anagrams), creativity (Torrance Test), and memory (Hopkins Verbal Learning Test) during actual and sham vagus nerve stimulation. Results: Vagus nerve stimulation impaired cognitive flexibility and creativity, but these results could not be explained by the induction of a general encephalopathy because VNS did not impair learning and improved retention. Conclusions: The means by which vagus nerve stimulation impairs cognitive flexibility and creative thinking is probably related to increased activity of the locus coeruleus-central adrenergic system that increases the signal-to-noise ratio and improves the brain's ability to attend to sensory input, but decreases its ability to recruit large-scale networks. © 2006 Elsevier Inc. All rights reserved.