Muscle sympathetic nerve activity is strongly activated during a static inflation of the lungs in awake human subjects. The purpose of the present study was to test the hypothesis that this sustained activation is due to the associated increase in intrathoracic pressure. In ten subjects microneurographic techniques were used to record muscle sympathetic activity from the peroneal nerve and arterial pressure was monitored continuously by finger-pulse photoplethysmography. Holding the breath at inspiratory capacity with the glottis closed and inspiratory muscles relaxed caused a sustained activation of muscle sympathetic nerve activity but not of skin sympathetic activity. Conversely, when subjects held the lungs maximally inflated by a constant inspiratory effort and an open glottis there was no sympathetic activation despite a similar initial fall in mean arterial pressure. Because intrathoracic pressure was below or close to atmospheric in the latter condition, it is concluded that a high intrathoracic pressure is required for the sympathetic response. Furthermore, the present results provide further support for the idea that unloading of cardiopulmonary baroreceptors is responsible for the sustained activation of muscle sympathetic nerve activity during static lung inflations in human subjects.