The aim of the present study is to report on the syndrome of sporadic major hyperekplexia during the neonatal period and early infancy, diagnosed in 39 patients at an average age of 3.3 months, the most severely affected during the first month of life. The patients mainly presented with marked irritability and recurrent startles in response to handling or even minute sounds, accompanied by rhythmic jerky movements and occasionally breath-holding episodes. Family history was negative for hyperekplexia, although eight parents reported jerky leg movements during sleep. The hallmark of hyperekplexia consisted of a hyper-alert gaze and an exaggerated startle with delayed habituation, also elicited by nose tapping and air blowing on the face accompanied by increasing rigidity. Nine severely affected infants, presenting with relentless startles, marked stiffness, violent rhythmic jerks, and breath-holding episodes were treated with oral low doses of clonazepam and completely recovered. Overall, the debilitating symptoms of hyperekplexia gradually resolved in all 39 infants, and their developmental assessment by 2 years of age was within the normal range. Therefore a prompt diagnosis of hyperekplexia during the neonatal period and early infancy, and then treatment if required with benzodiazepines to alleviate the debilitating symptoms, may prevent life-threatening events and enable better feeding and handling. Establishing the diagnosis of such a relatively benign disorder with a favorable developmental outcome may avoid unjustified extensive investigations or unnecessary treatment, suspecting an ominous progressive neurologic disorder.