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Induction of hypoxia-inducible-factor-1&#945; (HIF-1&#945;) pathway and HIF-target genes allow adaptation to hypoxia and are associated with reduced incidence of acute mountain sickness (AMS). Little is known about HIF-pathways in conjunction with inflammation or exercise stimuli under acute hypobaric hypoxia in non-acclimatized individuals. We therefore tested the hypotheses that (1) both hypoxic and inflammatory stimuli induce hypoxic-inflammatory signaling pathways in vitro, (2) similar results are seen in vivo under hypobaric hypoxia, and (3) induction of HIF-dependent genes is associated with AMS in 11 volunteers. In vitro, peripheral blood mononuclear cells (PBMCs) were incubated under hypoxic (10%/5% O₂) or inflammatory (CD3/CD28) conditions. In vivo, Interleukin 1&#946; (IL-1&#946;), C-X-C Chemokine receptor type 4 (CXCR-4), and C-C Chemokine receptor type 2 (CCR-2) mRNA expression, cytokines and receptors were analyzed under normoxia (520 m above sea level (a.s.l.)), hypobaric hypoxia (3883 m a.s.l.) before/after exercise, and after 24 h under hypobaric hypoxia. In vitro, isolated hypoxic (<i>p</i> = 0.004) or inflammatory (<i>p</i> = 0.006) stimuli induced IL-1&#946; mRNA expression. CCR-2 mRNA expression increased under hypoxia (<i>p</i> = 0.005); CXCR-4 mRNA expression remained unchanged. In vivo, cytokines, receptors, and IL-1&#946;, CCR-2 and CXCR-4 mRNA expression increased under hypobaric hypoxia after 24 h (all <i>p</i> &#8804; 0.05). Of note, proinflammatory IL-1&#946; and CXCR-4 mRNA expression changes were associated with symptoms of AMS. Thus, hypoxic-inflammatory pathways are differentially regulated, as combined hypoxic and exercise stimulus was stronger in vivo than isolated hypoxic or inflammatory stimulation in vitro.