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Background: Spaceflight is associated with immune dysregulation which is considered as risk factor for the performance of exploration-class missions. Among the consequences of confinement and other environmental factors of living in hostile environments, the role of different oxygen concentrations is of importance as either low (e.g. as considered for lunar or Martian habitats) or high (e.g. during extravehicular activities) can trigger immune dysfunction. The aim of this study was to investigate the impact of increased oxygen availability--generated through hyperbaricity--on innate immune functions in the course of a 14 days NEEMO mission., Methods: 6 male subjects were included into a 14 days undersea deployment at the Aquarius station (Key Largo, FL, USA). The underwater habitat is located at an operating depth of 47 ft. The 2.5 times higher atmospheric pressure in the habitat leads to hyperoxia. The collection of biological samples occurred 6 days before (L-6), at day 7 (MD7) and 11/13 (MD11/13) during the mission, and 90 days thereafter (R). Blood analyses included differential blood cell count, ex vivo innate immune activation status and inhibitory competences of granulocytes., Results: The absolute leukocyte count showed an increase during deployment as well as the granulocyte and monocyte count. Lymphocyte count was decreased on MD7. The assessments of native adhesion molecules on granulocytes (CD11b, CD62L) indicated a highly significant cellular activation (L-6 vs. MD7/MD13) during mission. In contrast, granulocytes were more sensitive towards anti-inflammatory stimuli (adenosine) on MD13., Conclusion: Living in the NEEMO habitat for 14 days induced significant immune alterations as seen by an activation of adhesion molecules and vice versa higher sensitivity towards inhibition. This investigation under hyperbaric hyperoxia is important especially for Astronauts' immune competence during extravehicular activities when exposed to similar conditions., (Copyright © 2015 Elsevier Inc. All rights reserved.)