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Introduction: About 500,000 people worldwide die annually from ruptured intracranial aneurysms (IA). The pathophysiology of aneurysm formation is largely unknown. Piezo1 mechanoreceptors are expressed in endothelial and smooth muscle cells of developing blood vessels. In addition to hemodynamic forces, Piezo1 has been shown to play an inflammatory role, as stiffness-sensing macrophages lacking Piezo1 exhibit reduced inflammation and enhanced wound healing responses. Malfunction of Piezo1 mechanoreceptors has been implicated in abdominal aortic aneurysm (AAA) development. With the increasing evidence of relationship between AAA and IAs, it is important to study Piezo1 dysregulation as a potential cause of IA development and/or rupture. Methods: During craniotomy for aneurysm clipping of ruptured and unruptured IAs, we excised and collected the aneurysm dome in four patients. Immunohistochemistry (IHC) was performed for Piezo1 and with CD31 to co-localize Piezo1 in the endothelial cells, and a-SMA to co-localize in smooth muscle cells on all aneurysm domes. Additional specimen was saved for genomic analyses. Results: Piezo1 mechanoreceptor overexpression was found in the smooth muscle layer of IAs, but not in superficial temporal artery (STA) controls, in all four human cerebral aneurysm domes. Additionally, there was significant dysregulation of Piezo1 mechanoreceptors in the IA compared with the regular appearance seen in the control human STA (Figure 1). Overexpression was not seen in human arteriovenous malformation specimens. Conclusions: Our data is the first demonstration of overexpression of Piezo1 mechanoreceptors in a disorganized manner in the walls of human IAs, which may represent a therapeutic target. We hypothesize that vascular shear stress leads to Piezo1-mediated disorganization in arterial smooth muscle cells and pro-inflammatory activation, which may lead to IA development and rupture.