Hypercapnic respiratory failure is common in advanced chronic obstructive pulmonary disease and is usually treated by nasal ventilation. Not all patients requiring such ventilation can tolerate it, with anxiety and phobia influencing their reaction, along with treatment failure. We report the case histories of six patients with hypercapnic respiratory failure who were at risk of death due to refusal of nasal ventilation or its failure despite ongoing treatment. We report their improvement with oral modafinil 200 mg tablets used as a respiratory stimulant, which led to discharge, improved arterial blood gases, and offset further admissions with hypercapnic respiratory failure. This drug is licensed for narcolepsy and is said to stimulate the respiratory system via the central nervous system. Its use in respiratory failure is an unlicensed indication, and there are no case reports or studies of such use in the literature. Its respiratory stimulant effects appear better than those with protriptyline, which was a drug previously used until its production was discontinued. Our findings suggest that a study of modafinil in hypercapnic respiratory failure would be warranted, especially for patients with treatment failure or intolerance to nasal ventilation. This may offer a way of shortening hospital stay, improving outcome and quality of life, and reducing death and readmissions.