Patients with disease of the ventilatory system, as opposed to disease of oxygenation, will develop hypERcapnoea as a result of hypoventilation or ventilation-perfusion mismatch.

Hypoventilation is the cause of type II respiratory failure in those with, for example, diaphragmatic muscle weakness or chest wall abnormality. In patients with severe COPD, for example, they will develop ventilation-perfusion mismatch, which will also cause hypercapnia (as well as hypoxaemia).

Some patients who are in type I respiratory failure may develop hypercapnia with worsening disease or acute exacerbations. They move from Type I respiratory failure to type II respiratory failure, which is associated with worse outcomes.