Respiratory failure is rarely a presenting symptom of motor neuron disease. Seven patients with motor neuron disease who presented with acute respiratory failure of unknown cause and required mechanical ventilation were studied. They all had symptoms and signs suggestive of diaphragmatic weakness. Respiratory involvement seemed disproportionately severe, as six were ambulatory and only three noted limb weakness. Only one had tongue weakness and none had swallowing difficulty. Electrophysiological studies showed widespread denervation and, in particular, diaphragmatic involvement to explain the severe respiratory failure. Weaning from the ventilator was unsuccessful in all cases. The four patients examined at necropsy showed severe loss of anterior horns cells in the cervical cord, with only minimal upper motor neuron involvement. Motor neuron disease should be recognised as a cause of acute respiratory failure, secondary to diaphragmatic paralysis from involvement of phrenic motor neurons.