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Background: Associations between personality traits and mental health outcomes (depression, anxiety, loneliness, and stress) have rarely been assessed in a population-representative sample of a high-income country during the COVID-19 pandemic. Additionally, as far as we know, the role of health and social behaviors as well as resilience in the personality-mental health relationship has yet to be explored. Methods: A representative sample of 1,828 residents of Luxembourg filled in validated scales to assess personality traits and resilience, depressive symptoms, generalized anxiety, loneliness, and stress, indicating mental health, in mid-April 2020. Results: Approximately 21% of the participants scored above the cut-off for moderate depression and moderate loneliness. Moderate anxiety and moderate stress were present in 6.2 and 0.3% of the participants, respectively. Higher-educated respondents and those living in higher-value housing reported better mental health. Agreeableness and conscientiousness were most consistently associated with better mental health; neuroticism was most consistently associated with worse mental health. Spending more time on social media was also associated with elevated levels of all four mental health outcomes. Social and health behaviors did not change the personality-mental health relationships. Resilience moderated some of the personality-mental health associations, most consistently in neuroticism. Conclusions: Findings suggest educational and socioeconomic inequalities in mental health in a nationally representative sample during the COVID-19 confinement measures. Personality traits, particularly agreeableness, conscientiousness, and low neuroticism were associated with mental health. The moderating role of resilience in the personality-mental health relationship suggests intervention potential to improve mental health during periods of confinement. [ABSTRACT FROM AUTHOR]