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Background NASA’s human exploration spaceflight missions to the Moon and Mars present unprecedented challenges for in-mission medical care. The distance from Earth will mean increased mission durations, communication delays, limited to no resupply opportunities, and constraints on the medical evacuation of astronauts. Mass, volume, power, and data will be limited while higher demands will be placed on the crew to manage medical care. NASA’s Moon to Mars exploration strategy lays out increasingly complex Artemis missions both in terms of duration and operations. In these more challenging deep space missions, it is important to quantitatively estimate the human medical risk to inform a traditional heuristic approach to medical risk. Prior tools have been developed for missions in low Earth orbit, but a new tool is required to plan for future exploration missions. Methods IMPACT (Informing Mission Planning via Analysis of Complex Tradespaces) is a risk assessment tool developed by NASA to advance exploration mission medical system design by quantitatively estimating mission medical risk. IMPACT v1.0 includes a novel evidence library baselined to exploration environments; an expanded list of 119 medical conditions; the addition of medical resources; and the ability for rapid and iterative analysis. Medical system risk estimates include loss of crew life, consideration of the need for return to definitive care (medical evacuation), and an estimate of crew time affected due to medical conditions. A notional long duration lunar orbit and lunar surface design reference mission (DRM) was chosen with a 4-astronaut crew to represent a sustained exploration Artemis mission. Results/Discussion Overall, IMPACT successfully quantified medical risk and derived an optimized medical system to support crew on a long duration lunar mission. In this DRM, the calculated loss of crew life from a medical event was 0.008 events per mission, risk of potential need for evacuation was 0.30 events per mission, and cumulative crew time affected by medical conditions was 103 days. The medical conditions that most contributed to overall medical risk were decompression sickness, trauma conditions, and respiratory failure. The conditions that had the largest effects on crew performance included musculoskeletal injuries and lunar dust exposure. The IMPACT-generated medical system included resources that target the most common and highest risk conditions. This systematic analysis demonstrates the value of the IMPACT tool in medical system design for human exploration spaceflight missions.