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Objective: Our primary aim was to investigate crew performance during medical emergencies with and without ground-support from a flight surgeon located at mission control., Background: There are gaps in knowledge regarding the potential for unanticipated in-flight medical events to affect crew health and capacity, and potentially compromise mission success. Additionally, ground support may be impaired or periodically absent during long duration missions., Method: We reviewed video recordings of 16 three-person flight crews each managing four unique medical events in a fully immersive spacecraft simulator. Crews were randomized to two conditions: with and without telemedical flight surgeon (FS) support. We assessed differences in technical performance, behavioral skills, and cognitive load between groups., Results: Crews with FS support performed better clinically, were rated higher on technical skills, and completed more clinical tasks from the medical checklists than crews without FS support. Crews with FS support also had better behavioral/non-technical skills (information exchange) and reported significantly lower cognitive demand during the medical event scenarios on the NASA-TLX scale, particularly in mental demand and temporal demand. There was no significant difference between groups in time to treat or in objective measures of cognitive demand derived from heart rate variability and electroencephalography., Conclusion: Medical checklists are necessary but not sufficient to support high levels of autonomous crew performance in the absence of real-time flight surgeon support., Application: Potential applications of this research include developing ground-based and in-flight training countermeasures; informing policy regarding autonomous spaceflight, and design of autonomous clinical decision support systems.