["The Journal of Physiology, EarlyView. ", "\nAbstract figure legend Participants completed cycling exercise with (placebo) and without (25 µg intrathecal fentanyl) intact group III/IV muscle afferent feedback in three settings: normoxia, acute hypoxia and chronic hypoxia after 7–9 days of acclimatisation (∼3800 m). Blocking afferent feedback suppressed exercise hyperpnoea across all environments, but resulted in larger reductions in arterial oxygenation in hypoxia. Fentanyl also attenuated the exercise‐induced increase in mean arterial pressure, with a greater blood pressure–lowering effect observed in hypoxia. In contrast circulating lactate and hydrogen ion concentration ([H+]) increased, particularly during acute hypoxia, with partial attenuation after acclimatisation. These findings demonstrate that group III/IV afferent feedback plays a critical role in maintaining arterial oxygenation and perfusion pressure during exercise, with heightened physiological importance in hypoxia where small disruptions to ventilatory control and cardiovascular regulation have amplified consequences for oxygen transport.\n\n\n\n\n\n\n\n\n\nAbstract\nGroup III/IV muscle afferents play a prominent role in ensuring appropriate arterial oxygenation during exercise. Exercise in hypoxia poses a major cardiorespiratory challenge due to reduced inspired oxygen pressure (PIO2). Although humans adapt powerfully to hypoxia, the contribution of group III/IV afferents to ventilatory, pressor and metabolic responses to exercise in chronic hypoxia remains unknown. Fourteen healthy participants completed cycling trials with (placebo) and without (25 µg intrathecal fentanyl) intact group III/IV afferent feedback in three settings: (1) normoxia, PIO2 = 139 mmHg;  (2) acute hypoxia, PIO2 = 90 mmHg; and (3) chronic hypoxia, after 7–9 days of acclimatisation to 3800 m, PIO2 = 90 mmHg. Participants completed three 3‐min stages at matched absolute intensities corresponding to 45%, 60% and 75% sea‐level maximal aerobic power. Ventilation, pulmonary gas exchange, arterial blood gases and blood pressure were measured. Fentanyl suppressed exercise hyperpnoea similarly across environments (P < 0.001) but produced larger reductions in arterial oxygenation in hypoxia, lowering saturation by ∼3%–5% and content by ∼0.7–1.0 ml dL−1 (condition×PIO2, P ≤ 0.016). Fentanyl also blunted the exercise‐induced increase in mean arterial pressure, with a greater blood pressure–lowering effect of –10 to 13 mmHg observed in hypoxia (condition×PIO2, P = 0.021). In contrast fentanyl increased circulating lactate and hydrogen ion concentration ([H+]) (P < 0.001), an effect accentuated during acute hypoxia (lactate: +1–2 mmol L−1, [H+]: +2–5 nmol L−1) but attenuated after acclimatisation (interactions, P ≤ 0.034). Thus group III/IV afferent feedback becomes more consequential in hypoxia, as small perturbations in ventilatory control and perfusion pressure have amplified consequences for oxygen transport.\n\n\n\n\n\n\n\n\n\nKey points\n\nGroup III/IV muscle afferent feedback contributes to normal exercise hyperpnoea and blood pressure regulation; whether its functional contribution is altered by acute and chronic hypoxia is unknown.\nIn a double‐blind, placebo‐controlled cross‐over design, 14 participants completed steady‐state cycling with intact (placebo) or attenuated (intrathecal fentanyl) group III/IV afferent feedback in normoxia, acute hypoxia and after 7–9 days of acclimatisation at 3800 m.\nIntrathecal fentanyl suppressed exercise hyperpnoea similarly across environments but caused exaggerated arterial oxygen desaturation during hypoxic exercise, reflecting operation on the steep portion of the oxygen–haemoglobin dissociation curve.\nThe blood pressure–lowering effect of intrathecal fentanyl was greater during hypoxic exercise; effects on metabolic strain were greatest in acute hypoxia and largely normalised after acclimatisation.\nThese findings highlight the functional importance of group III/IV muscle afferent feedback during hypoxic exercise, where small perturbations in ventilatory and pressor control have amplified consequences for oxygen transport.\n\n\n"]