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Uncontrolled hypertension (HTN) is growing in incidence globally creating a critical need for alternative therapeutic strategies. Directly stimulating the carotid sinus nerve (CSN) is known to potentially reduce blood pressure (BP) but its clinical efficacy has not been consistently demonstrated with existing electrode technologies in humans. We investigated the effect of acute direct CSN stimulation on BP and HR in anesthetized humans using an application-specific multi-contact electrode. Using a novel surgical approach, a custom electrode was implanted around tissue including CSN branches in anesthetized adults. Following functional mapping, presumed baroafferent fibers were identified via response and stimulated. Outcome measures included change in systolic BP (SBP), diastolic BP (DBP), and heart rate (HR) during and after stimulation using multi-level modeling. Secondarily, dose dependency was examined. In 13 subjects, stimulation caused a 24 ± 20 mmHg (mean ± SD, p < 0.01) maximum drop in SBP, with associated drops in DBP (11 ± 9 mmHg, p < 0.01) and HR (10 ± 9 bpm, p < 0.05). In subjects with baseline SBP > 120 mmHg (n = 8), maximum SBP drop was 31 ± 23 mmHg, while subjects with baseline SBP < 120 mmHg (n = 5) exhibited a maximum SBP drop of 11 ± 3 mmHg. In all patients, BP and HR recovered rapidly with stimulus withdrawal. There were results suggesting a positive dose (electrical current) response relationship. Using a novel surgical approach and application specific electrode, direct stimulation of the carotid sinus nerve in anesthetized human subjects caused a marked concurrent drop in BP/HR followed by rapid recovery with stimulation withdrawal. There was an indication of dose dependency.This study was registered as ClinicalTrials.gov ID NCT06969846, May 9, 2025.