Thyrotropin-releasing hormone (TRH) stimulates pituitary thyrotropin synthesis and release and also regulates autonomic nervous system functions by acting as a neuromodulator and neurotransmitter. In experimental animals a stimulation of ventilation by thyrotropin-releasing hormone was shown when applied at central nervous system sites that affect respiratory motor output. It was the goal of our study to investigate the respiratory properties of thyrotropin-releasing hormone on basal and stimulated (i.e. CO2-rebreathing) conditions following systemic thyrotropin-releasing hormone application in healthy humans. Thyrotropin-releasing hormone (200 micrograms, 400 micrograms intravenous) initiated a rapid short lasting rise of minute volume, ventilatory air-flow and alveolar oxygen tension under steady state breathing (P less than 0.001). Breathing frequency was less affected, heart rate rose concomitantly (P less than 0.001). While breathing with increasing concentrations of carbon dioxide, minute volume was higher under thyrotropin-releasing hormone than under placebo alone. Further effects (e.g. nausea, dizziness, palpitations) mostly appeared later than respiratory changes and thus may not be responsible for their initiation. Our findings prove systemic thyrotropin-releasing hormone to be a strong respiratory stimulant in man. Response in respiratory output was also accompanied by central nervous system-effects (e.g. dizziness, restlessness, augmented vigilance). The mode of thyrotropin-releasing hormone effects on respiration after peripheral administration is still speculative. An augmented sympathetic output or a direct receptor mediated action at central nervous system sites may be responsible, while a peripheral effect cannot be excluded.