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Pimavanserin is a highly selective 5-HT 2A inverse agonist in current medical use. Prior studies suggest that 5-HT 2A serotonin receptors may play a role in anxiety and emotional memory. Therefore, pimavanserin was tested in a rat model of PTSD to determine whether it might ameliorate PTSD-like symptoms. The lifetime prevalence of PTSD is estimated to be 125% higher in women than men. Consequently, in an effort to create a robust model of PTSD that was more representative of human PTSD prevalence, 20-week old female rats of the emotionally hyperreactive Lewis strain were used for these studies. The rats were single-housed and exposed twice to restraint stress coupled with predator odor or to a sham-stressed condition. Twenty days after the second stress or sham-stress exposure, rats were injected with saline alone or with 0.3 or 1.0 mg/kg pimavanserin, doses that were confirmed to substantially block 5-HT 2A receptor activity in this study without causing any non-specific behavioral or adverse effects. One hour later, rats were tested for anxiety through acoustic startle response, the elevated plus-maze and three parameters of open field behavior. Five days later, blood was sampled for plasma corticosterone. The stressed/saline-injected rats had higher anxiety scores and corticosterone levels than sham-stressed/saline-injected rats. Pimavanserin significantly and generally dose-dependently reversed these persistent stress effects, but had no significant effect on the behavioral measures in normal, non-stressed rats. These results, consistent with a role for the 5-HT 2A receptor, suggest that pimavanserin might have potential to reduce some consequences of traumatic stress., Competing Interests: Declaration of competing interest Supported by funding from Acadia Pharmaceuticals Inc. to the University of Houston-Clear Lake, and by the University of Houston-clear Lake Biobehavioral Research Fund. Co-author Ethan S. Burstein is an employee of Acadia Pharmaceuticals., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)