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Clozapine is an atypical antipsychotic used in refractory schizophrenia and depression. Its use is often complicated by its vast side-effect profile including cardiovascular reactions, agranulocytosis, and seizures. Specifically, the cardiac complications of clozapine have been shown to predominantly cause myocarditis and pericarditis. In this case report, the case of a 58-year-old male being treated for treatment-resistant depression and schizophrenia who suffers from tachycardia is presented. He is treated empirically for orthostatic hypotension with IV fluids without much success. Further imaging and echocardiography demonstrated a pericardial effusion, a rare reaction (≤1 : 10000) that has only been documented in a handful of case reports. This anecdotal evidence highlights the significance of polyserositis/pericardial effusion in the context of clozapine-induced orthostatic hypotension resistant to rehydration. When starting a patient on clozapine, it is important to consider further workup and monitoring with laboratory baseline biomarkers and cardiac evaluation with symptomatic individuals. Upon immediate cessation of clozapine, the pericardial effusion should spontaneously resolve without complication and should not be rechallenged., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Nathan Gilbreth et al.)