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In space, living organisms are exposed to numerous stress factors including microgravity and space radiation. For humans, these harmful environmental factors have been known to cause negative health impacts such as immune dysfunction. Understanding the mechanisms by which spaceflight impacts human health at the molecular level is critical not only for accurately assessing the risks associated with spaceflight, but also for developing effective countermeasures. This study is part of the Functional Immune Project, intended to determine alterations in crewmembers` immunobiology before, during, and after spaceflight. For this project, blood samples were collected from International Space Station (ISS) crewmembers at the following time points: i) Blood was drawn at two pre-flight time points of 180 days (L180) and 45 days (L45) before launch. ii) During flight, blood was drawn at approximately the midpoint (mid-flight, MF) of the mission, and shortly before egress from the ISS (late-flight, LF). iii) Post-flight blood samples were collected within 36 hours (R0), 30 days (R30) and 90 days (R90) after landing. For each crewmember, blood was also drawn from a matching test subject on the ground at the corresponding time point. For both the ISS crewmembers and the ground control subjects, total RNA was isolated from peripheral blood mononuclear cells (PBMC) and mRNA was analysed using next generation RNA-sequencing (NGS). Differentially expressed genes were determined by performing contrast analysis. Using the ground control subjects of all time points combined as a control, a number of dysregulated genes were identified in astronauts at MF, LF and R0, including downregulations of SMAD7 and CDKN1A at MF and LF. Some of the genes such as SERPINE1 and VEGFA were downregulated at MF and LF, but upregulated at R0, while others such as NKG7 were down regulated at all 3 time points. Pathway analysis of these differentially expressed genes indicated that the NF-κB pathway was chronically activated in space. Analysis of the consequent diseases suggested potential associations with not only immune dysfunction, but also other health risks including osteoarthritis, cardiac hypertrophy and neuroinflammation.