INTRODUCTION: Repeated ischemic preconditioning (IPC) can improve muscle and pulmonary oxygen on-kinetics, blood flow, and exercise efficiency, but these effects have not been investigated in severe hypoxia. The aim of the current study was to evaluate the effects of 7 d of IPC on resting and exercising muscle and cardio-pulmonary responses to severe hypoxia.METHODS: A total of 14 subjects received either: 1) 7 d of repeated lower-limb occlusion (4 × 5 min, 217 ± 30 mmHg) at limb occlusive pressure (IPC) or SHAM (4 × 5 min, 20 mmHg). Subjects were tested for resting limb blood flow, relative microvascular deoxyhemoglobin concentration ([HHB]), and pulmonary oxygen (Vo_2p) responses to steady state and incremental exercise to exhaustion in hypoxia (fractional inspired O₂ = 0.103), which was followed by 7 d of IPC or SHAM and retesting 72 h post-intervention.RESULTS: There were no effects of IPC on maximal oxygen consumption, time to exhaustion during the incremental test, or minute ventilation and arterial oxygen saturation. However, the IPC group had higher delta efficiency based on pooled results and lower steady state Δ[HHB] (IPC ∼24% vs. SHAM ∼6% pre to post), as well as slowing the [HHB] time constant (IPC ∼26% vs. SHAM ∼3% pre to post) and reducing the overshoot in [HHB]: Vo₂ ratio during exercise onset.CONCLUSIONS: Collectively, these results demonstrate that muscle O₂ efficiency and microvascular O₂ distribution can be improved by repeated IPC, but there are no effects on maximal exercise capacity in severe hypoxia.Chopra K, Jeffries O, Tallent J, Heffernan S, Kilduff L, Gray A, Waldron M. Repeated ischemic preconditioning effects on physiological responses to hypoxic exercise. Aerosp Med Hum Perform. 2022; 93(1):13–21.