Water ingestion induces a robust increase in blood pressure in patients with baroreflex impairment. To better understand this phenomenon, we use a modified sino‐aortic denervated mouse model. Water (750μL/30g body weight), but not saline solution, infused into the duodenum of these mice stimulates an increase in blood pressure (BP) similar in magnitude and time course to that in patients. This indicates that hypo‐osmolality is the stimulus for this response. Previous studies provided evidence that increased sympathetic outflow underlies this pressor effect. However, physiological and molecular mediators of this effect remain unknown. Calcitonin Gene Related Peptide (CGRP) exerts effects centrally and peripherally in the gastrointestinal, respiratory and endocrine systems. It has been implicated in conveying afferent information that leads to sympathetic activation in response to sensory input. To determine whether CGRP plays a crucial role in the osmopressor response, water was given intraduodenally to sino‐aortic denervated α‐CGRP −/−mice. Although CGRP−/− mice had higher baseline BP before denervation (MAP = 82 ± 2 mmHg in CGRP−/− mice compared to 77 ± 2 mmHg in the WT, P value<0.001), the magnitude of BP increase after water infusion was similar in the knockout (ΔMAP= 14.4 ± 5 mmHg) and wild type mice (ΔMAP= 15.9 ± 4 mmHg) (P value = 0.49). This indicates that CGRP is not required for the pressor effect of water.