Hypoxia-sensitive peripheral carotid chemoreceptors, which regulate sympathetic outflow from the brain stem, are promising antihypertensive treatment targets. However, the central nervous pathways integrating human peripheral chemoreflexes are poorly understood. We combined high-resolution functional magnetic resonance imaging with physiological profiling to elucidate hypothalamic and medullary responses to acute hypoxia. We exposed 12 healthy men (29.7±6.6 years) to 5 hypoxic episodes each by breathing 10% oxygen for 180 seconds followed by 90 seconds of normoxia during high-resolution subcortical functional magnetic resonance imaging. We recorded beat-by-beat finger blood pressure, ECG, and peripheral oxygen saturation (Sp o ₂ ). We analyzed functional magnetic resonance imaging data through independent component analysis, correlation with systolic blood pressure and Sp o ₂ , and functional connectivity analysis by dual regression. On average Sp o ₂ decreased by 12±3% ( P <0.01) during hypoxia while heart rate increased by 3±7 bpm ( P <0.01). Systolic blood pressure was unchanged. Brain stem-centered analyses revealed 5 distinct hypoxia-responsive regions around the nucleus of the solitary tract, nucleus ambiguus/intermediate reticular nucleus, dorsal motor nucleus of the vagal nerve, spinal trigeminal nucleus, and inferior olivary nucleus. Hypothalamus-centered analysis revealed 3 such regions around the arcuate nucleus, anterior hypothalamic area/lateral hypothalamic area, and paraventricular nucleus. During hypoxia, these regions showed altered functional connectivity with various medullary and hypothalamic areas. We conclude that high-resolution functional magnetic resonance imaging reveals subcortical systems engaged by acute hypoxia, which likely correspond to the peripheral chemoreceptor pathway. Our methodology may have utility in studying peripheral chemoreflex contributions to cardiovascular disease and responses to peripheral chemoreceptor modulation. Registration: URL: https://www.drks.de/ . Unique identifier: DRKS00013101.