Aim Experiments have indicated that skin perfusion in mice is sensitive to reductions in environmental O2 availability. Specifically, a reduction in skin‐surface PO2 attenuates transcutaneous O2 diffusion, and hence epidermal O2 supply. In response, epidermal HIF‐1α expression increases and facilitates initial cutaneous vasoconstriction and subsequent nitric oxide‐dependent vasodilation. Here, we investigated whether the same mechanism exists in humans. Methods In a first experiment, eight males rested twice for 8 h in a hypobaric chamber. Once, barometric pressure was reduced by 50%, while systemic oxygenation was preserved by O2‐enriched (42%) breathing gas (HypoxiaSkin), and once barometric pressure and inspired O2 fraction were normal (Control1). In a second experiment, nine males rested for 8 h with both forearms wrapped in plastic bags. O2 was expelled from one bag by nitrogen flushing (AnoxiaSkin), whereas the other bag was flushed with air (Control2). In both experiments, skin blood flux was assessed by laser Doppler on the dorsal forearm, and HIF‐1α expression was determined by immunohistochemical staining in forearm skin biopsies. Results Skin blood flux during HypoxiaSkin and AnoxiaSkin remained similar to the corresponding Control trial (P = 0.67 and P = 0.81). Immunohistochemically stained epidermal HIF‐1α was detected on 8.2 ± 6.1 and 5.3 ± 5.7% of the analysed area during HypoxiaSkin and Control1 (P = 0.30) and on 2.3 ± 1.8 and 2.4 ± 1.8% during AnoxiaSkin and Control2 (P = 0.90) respectively. Conclusion Reductions in skin‐surface PO2 do not affect skin perfusion in humans. The unchanged epidermal HIF‐1α expression suggests that epidermal O2 homoeostasis was not disturbed by HypoxiaSkin/AnoxiaSkin, potentially due to compensatory increases in arterial O2 extraction.