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Prior work suggests perceived COVID-19-related threat and existential isolation (EI) would be associated with greater anxiety and depression, worse subjective health and well-being, and lower hope. However, it was unclear whether such concerns might have additive effects (no interaction, two independent main effects) or interact (one effect modifies the other). Two studies collected data via MTurk during the COVID-19 pandemic. Study 1 (N = 110) measured perceived COVID19-related threat, EI, anxiety and depression, subjective well-being, and hope. Study 2 (N = 2,673) measured perceived COVID19-related threat, EI, anxiety, subjective health, and hope. In general, perceived COVID19-related threat and EI were associated with anxiety and depression, worse subjective health and well-being, and reduced hope. On one outcome (hope, Study 2), an interaction was observed: perceived threat was associated with lower hope among those with high EI, but higher hope among those with low EI. However, on most outcomes (6 of 7), across both studies, additive effects were observed: greater cumulative existential stress (perceived COVID-19-related threat, EI) was associated with worse anxiety and depression, subjective health and well-being, and hope. Discussion highlights theoretical considerations, practical implications, and the therapeutic value of addressing existential concerns in mental health. What is already known about this topic:Prior work found perceived COVID-19-related threat and other death-related existential concerns were related to anxiety, depression, and undermined well-being and hopeful engagement.Prior work found existential isolation was related to anxiety, depression, and undermined well-being.COVID-19-related threat was associated with worse anxiety, depression, and well-being, but not subjective health or hope. Prior work found perceived COVID-19-related threat and other death-related existential concerns were related to anxiety, depression, and undermined well-being and hopeful engagement. Prior work found existential isolation was related to anxiety, depression, and undermined well-being. COVID-19-related threat was associated with worse anxiety, depression, and well-being, but not subjective health or hope. What this topic adds:EI was consistently associated with worse anxiety and depression, subjective health and well-being, and reduced hope.In one outcome (hope, Study 2), an interaction found that perceived COVID-19-related threat decreased hope when people felt existentially isolated, but increased hope when people felt a sense of existential connection (e.g., “we’re all in this together”).However, on six of seven outcomes, across two studies, additive effects were observed such that the more existential stress (COVID-19-related threat, existential isolation) experienced the worse the outcome. EI was consistently associated with worse anxiety and depression, subjective health and well-being, and reduced hope. In one outcome (hope, Study 2), an interaction found that perceived COVID-19-related threat decreased hope when people felt existentially isolated, but increased hope when people felt a sense of existential connection (e.g., “we’re all in this together”). However, on six of seven outcomes, across two studies, additive effects were observed such that the more existential stress (COVID-19-related threat, existential isolation) experienced the worse the outcome.