We examined the contribution of the neural elements near the ventral medullary surface (VMS) to the respiratory response caused by 2,4-dinitrophenol (DNP). Two series of experiments were performed on 12 vagotomized and sinoaortic denervated cats. The first series examined the effect of focal cooling of the VMS on the respiratory response to DNP in four spontaneously breathing, anesthetized cats. When the VMS temperature was 37 degrees C, systemic administration of DNP increased minute ventilation under nearly isocapnic conditions, and focal cooling of the intermediate area of VMS to 20 degrees C attenuated the ventilatory augmentation caused by DNP. To eliminate the influence of anesthetics, a second group of experiments was performed on eight decerebrate, artificially ventilated cats while phrenic nerve activity was monitored as an index of respiration. AgNO3 (10%) was topically applied to the VMS until the respiratory response to inhaled CO2 was abolished. Apnea occurred in seven of eight cats after AgNO3, whereas in the remaining one animal, tidal phrenic activity decreased substantially. Systemic administration of DNP produced no respiratory excitation in any of the animals. On the other hand, rhythmic respiratory activity could be provoked by electrical stimulation of the mesencephalic locomotor area and carotid sinus nerve and by excitation of somatic afferents. Histological examination of the brain stem showed that the AgNO3 had penetrated no more than 350 microns from the ventral medullary surface. These results indicate superficial structures of the VMS are of potential importance in mediating the respiratory responses to hypermetabolism.