Congenital hypertrophic pyloric stenosis (CHPS) is a common condition in infancy associated with smooth muscle hypertrophy and resulting in pyloric outlet obstruction. The final diagnosis of CHPS is based on precise ultrasonographic measurements of length and width of the pyloric muscle. Based on our clinical and sonographic experience, we observed that smaller measurements of the pyloric muscle were obtained in dehydrated infants than in children examined after proper fluid restoration. The clinical importance of these observations was evident because false-negative results could be obtained. An experimental animal work followed, proving our clinical observation to be true. A significant difference of about 30% to 50% was found between measurements of the muscle thickness of the gastric and pyloric muscles in a state of water deprivation, as compared with a state of full hydration (p < 0.05). Based on our preliminary results, we suggest that children with suspected CHPS should be well hydrated before the ultrasound (US) examination is performed, to avoid false-negative results and a consequent delay in treatment.