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Non-human primate (NHP) models are essential for developing and translating new treatments that target neural circuit dysfunction underlying human psychopathology. As a proof-of-concept for treating neuropsychiatric disorders, we used a NHP model of pathological anxiety to investigate the feasibility of decreasing anxiety by chemogenetically (DREADDs [designer receptors exclusively activated by designer drugs]) reducing amygdala neuronal activity. Intraoperative MRI surgery was used to infect dorsal amygdala neurons with AAV5-hSyn-HA-hM4Di in young rhesus monkeys. In vivo microPET studies with [ 11 C]-deschloroclozapine and postmortem autoradiography with [ 3 H]-clozapine demonstrated selective hM4Di binding in the amygdala, and neuronal expression of hM4Di was confirmed with immunohistochemistry. Additionally, because of its high affinity for DREADDs, and its approved use in humans, we developed an individualized, low-dose clozapine administration strategy to induce DREADD-mediated amygdala inhibition. Compared to controls, clozapine selectively decreased anxiety-related freezing behavior in the human intruder paradigm in hM4Di-expressing monkeys, while coo vocalizations and locomotion were unaffected. These results are an important step in establishing chemogenetic strategies for patients with refractory neuropsychiatric disorders in which amygdala alterations are central to disease pathophysiology., Competing Interests: Declaration of interests N.H.K. currently receives research support from the National Institute of Mental Health; serves as a consultant to CME Outfitters, the Pritzker Neurospsychiatric Disorders Research Consortium, Skyland Trail Advisory Board, and the Institute of Early Adversity Research External Scientific Advisory Board at the University of Texas – Austin; is a shareholder in Seattle Genetics; has served as co-editor of Psychoneuroendocrinology, and currently serves as Editor-in-Chief of The American Journal of Psychiatry. All other authors report no biomedical financial interests or potential declarations of interest., (Copyright © 2021 The American Society of Gene and Cell Therapy. All rights reserved.)