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Background: Low serum chloride (Cl − ) level is considered an independent predictor of cardiovascular mortality associated with chronic hypertension. However, the underlying mechanisms are unknown. ClC-5, a member of the Cl − channel family, is sensitive to changes in intracellular and extracellular Cl − concentration and conducts outwardly rectifying Cl − currents. The aims of this study were to determine if ClC-5 is regulated by low extracellular Cl − , clarify its putative roles in hypertension-induced cerebrovascular remodeling, and elucidate the associated underlying mechanisms. Methods: Whole-cell patch technique, intracellular Cl − concentration measurements, flow cytometry, Western blot, Clcn5 knockdown (Clcn5 −/y ), and adenovirus-mediated ClC-5 overexpression mice, 2-kidney, 2-clip, and angiotensin II infusion–induced hypertensive models were used. Results: We found that low extracellular Cl − evoked a ClC-5–dependent Cl − current that was abolished by ClC-5 depletion in basilar artery smooth muscle cells. ClC-5 was upregulated in the arterial tissues of rats and patients with hypertension. Low Cl − –induced current and ClC-5 protein expression positively correlated with basilar artery remodeling during hypertension. ClC-5 knockdown ameliorated hypertension-induced cerebrovascular remodeling and smooth muscle cell proliferation, whereas ClC-5 overexpression mice exhibited the opposite phenotype. ClC-5–dependent Cl − efflux induced by low extracellular Cl − activated WNK1 (lysine-deficient protein kinase 1) which, in turn, activated AKT, and culminated in basilar artery smooth muscle cell proliferation and vascular remodeling. Conclusions: ClC-5 mediates low Cl − –induced Cl − currents in basilar artery smooth muscle cells and regulates hypertension-induced cerebrovascular remodeling by promoting basilar artery smooth muscle cell proliferation via the WNK1/AKT signaling pathway.