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Salivary flow rate, immunoglobulin, and periodontal status were affected during a simulated Skylab mission. The effect is more prominent after long-duration space flights and can persist for several weeks after landing. The objective of this study was to determine the effect of a simulated Mars environment on periodontal status and levels of salivary microorganisms and immunoglobulins in the human oral cavity. Twelve healthy male volunteers were studied before, at 1 and 2 weeks, and after completion of a mission in an isolated, confined simulated Mars environment at the Mars Desert Research Station, USA. We conducted a current stress test, measured salivary immunoglobulin, cortisol, a-amylase, salivary flow rate, and levels of plaque and salivary microbes, and assessed clinical periodontal parameters (probing depth, bleeding on probing, and clinical loss of attachment). Salivary IgG levels and Streptococcus mutans activity were significantly higher at 1 week. Values for clinical periodontal parameters (probing depth, bleeding on probing, and clinical loss of attachment) significantly differed at 1 week. Stress might be caused by the difficulty of the mission rather than the isolated environment, as mission duration was quite short. Periodontal condition might worsen due to poor oral hygiene during the mission. The present findings show that all periodontal conditions and levels of oral bacteria and stress after completion of the simulated Mars mission differed from those at baseline. To verify the relationship between stress status and periodontal health in simulated Mars missions, future studies using larger patient samples and longer follow-up will be required.