In our previous animal studies on dogs, regulation of breathing was found to be altered after en bloc transplantation of the heart and both lungs. During carbon dioxide (CO2) inhalation the minute volume was increased due to an increase of tidal volume after transplantation whereas before transplantation both respiratory frequency and tidal volume increased. The success of the heart-lung transplantation was based on experiments on baboons as no long-term survivors were obtained in dogs. It was thought that the regulation of breathing is different in dogs and primates. We therefore decided to study the regulation of breathing in humans after bilateral lung transplantation during CO2 stimulation. The regulation of breathing was tested 2 to 4 months after bilateral lung transplantation in six patients. Six healthy subjects with intact lungs were tested as controls. The test persons were allowed to breathe first room air, then 5% CO2 in air for 4 min and then room air again. The frequency of respiration, tidal volume and minute ventilation were recorded using a phneumotachograph. Simultaneously samples of arterial blood were drawn from a cannulated brachial artery for analysis of pressure of arterial oxygen (PaO2), pressure of arterial carbon dioxide (PaCO2), base excess (BE) and pH. During inhalation of CO2 for 4 min the minute volume doubled in both transplant patients and in controls. The tidal volume of the transplant patients increased significantly more than that of the controls (P < 0.005) whereas respiratory frequency increased significantly only in the controls with intact lungs (P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)