BACKGROUND: The Aerospace Medicine Systematic Review Group was set up in 2016 to facilitate high quality and transparent synthesis of primary data to enable evidence-based practice. The group identified many research methods specific to space medicine that need consideration for systematic review methods. The group has developed space medicine specific methods to address this and trialed usage of these methods across seven published systematic reviews. This paper outlines evolution of space medicine synthesis methods and discussion of their initial application.METHODS: Space medicine systematic review guidance has been developed for protocol planning, quantitative and qualitative synthesis, sourcing gray data, and assessing quality and transferability of space medicine human spaceflight simulation study environments.RESULTS: Decision algorithms for guidance and tool usage were created based on usage. Six reviews used quantitative methods in which no meta-analyses were possible due to lack of controlled trials or reporting issues. All reviews scored the quality and transferability of space simulation environments. One review was qualitative. Several research gaps were identified.CONCLUSION: Successful use of the developed methods demonstrates usability and initial validity. The current space medicine evidence base resulting in no meta-analyses being possible shows the need for standardized guidance on how to synthesize data in this field. It also provides evidence to call for increasing use of controlled trials, standardizing outcome measures, and improving minimum reporting standards. Space medicine is a unique field of medical research that requires specific systematic review methods.Winnard A, Caplan N, Bruce-Martin C, Swain P, Velho R, Meroni R, Wotring V, Damann V, Weber T, Evetts S, Laws J. Developing, implementing, and applying novel techniques during systematic reviews of primary space medicine data. Aerosp Med Hum Perform. 2021; 92(8):681688.