The relative contributions of peripheral neuromuscular and central nervous system components in the respiratory failure following acute exposure to organophosphorous anticholinesterase (AChE) agents remain unclear. We examined the effects of the nerve agents, soman, sarin, tabun, and VX on diaphragm contraction, diaphragm electromyogram (EMG), phrenic nerve activity, medullary respiratory-related unit activity, and airflow in the cat. The agents were infused at the rate of 1 LD50 per 15 minutes until respiratory arrest, at which time the phrenic nerve was stimulated supramaximally to test diaphragmic contraction. We found that one of the first signs of respiratory distress is disruption of the normal firing pattern of the medullary respiratory-related neurons. This is followed by changes in phrenic nerve activity, diaphragm EMG, diaphragm contraction and airflow. At the time of respiratory arrest, the medullary respiratory-related units and the phrenic nerve have stopped firing. Immediately following cessation of spontaneous respiration, the diaphragm was tested by stimulating the phrenic nerve with 2 msec pulses of 500 msec duration at 10 Hz and at 100 Hz. Stimulation at 10 Hz consistently produced a frequency-following contraction, while stimulation at 100 Hz produced a tetanic contraction. We conclude that loss of central respiratory drive is the predominant cause of nerve agent-induced respiratory failure, as the diaphragm muscle still contracts tetanically when challenged with a 100 Hz train for 500 msec at the time of respiratory arrest.