Difficult weaning from mechanical ventilation is a major problem in critically ill patients. The pathophysiology of weaning failure is complex and multiple causes for difficult weaning may exist in any single patient. We have recently developed a structural framework ('ABCDE') for the assessment and treatment of difficult-to-wean patients. In this article, we present the case of a difficult-to-wean 68-year-old male with chronic obstructive pulmonary disease who had been on mechanical ventilation for three weeks. The patient was referred to our centre for assessment of the cause of weaning failure. During a spontaneous breathing trial at our centre an extensive physiological evaluation revealed diastolic dysfunction as the most important cause for weaning failure. It was advised to titrate continuous intravenous nitroglycerin to control systolic blood pressure during subsequent spontaneous breathing trials. In addition, oral antihypertensive drugs were added to control hypertension throughout the day. After treatment in the referring hospital, the patient was successfully weaned from mechanical ventilation within one week. This case report illustrates that a structured approach to weaning failure can unmask hidden pathology and help in the development of a tailored treatment strategy.