According to the classical international guidelines, non-invasive ventilation is contraindicated in hypercapnic encephalopathy syndrome (HES) due to the poor compliance to ventilatory treatment of confused/agitated patients and the risk of aspirative pneumonia related to lack of airways protection. As a matter of fact, conventional mechanical ventilation has been recommended as "golden standard" in these patients. However, up to now there are not controlled data that have demonstrated in HES the advantage of conventional mechanical ventilation vs non-invasive ventilation. In fact, patients with altered mental status have been systematically excluded from the randomised and controlled trials performed with non-invasive ventilation in hypercapnic acute respiratory failure. Recent studies have clearly demonstrated that an initial cautious NPPV trial in selected HES patients may be attempt as long as there are no other contraindications and the technique is provided by experienced caregivers in a closely monitored setting where ETI is always readily available. The purpose of this review is to report the physiologic rationale, the clinical feasibility and the still open questions about the careful use of non-invasive ventilation in HES as first-line ventilatory strategy in place of conventional mechanical ventilation via endotracheal intubation.