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Smoking is one of the leading causes of preventable death worldwide. Several pharmacological therapies have been established over the years to aid in smoking cessation, including Varenicline, a partial nicotine agonist. Neuropsychiatric adverse events have been reported in patients treated with Varenicline. Here, we present a case of first-episode psychosis in the context of Varenicline therapy. The patient's chart was retrospectively reviewed for relevant medical and psychiatric history, in addition to the use of current or past medications. Routine laboratory investigations and brain imaging were performed. The Naranjo Adverse Drug Reaction Probability Scale was also done independently by two physicians involved in the patient's treatment. He was admitted for psychotic symptoms elicited in the context of a probable adverse reaction to Varenicline. The current evidence linking Varenicline to psychosis remains controversial. Speculatively, there could be a link between Varenicline, which supposedly increases dopamine levels in the prefrontal cortex through the mesolimbic pathways, and psychotic symptoms. It is therefore beneficial to be cognizant, in a clinical setting, of the possibility of the emergence of these symptoms with Varenicline therapy., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Zoghbi et al.)