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Different professionals (e.g. in the military) have to perform cognitive challenging tasks in multi-stressor environments. However, our understanding how combined stressors interact and affect cognitive performance is limited (Van Dongen & Belenky, 2009). This study examined how sleep deprivation (SD) and acute social stress affect cognitive performance in isolation and in combination, and used a comprehensive approach to find evidence for a (shared) mechanism. Recent research suggests that SD leads to higher amounts of proinflammatory markers (i.e. cytokines) in the blood, which assumedly contribute to a decline in cognitive performance (Irwin, 2019; Shields et al., 2017). In addition, acute social stressors have also been shown to elicit an immune response, as reflected by circulating cytokines in blood (Marsland et al., 2017; Prather et al., 2014). These findings suggest that different stressors may affect cognitive performance through an effect on the immune system. We therefore hypothesize that individuals showing a high proinflammatory response to a combination of two stressors (SD and acute social stress) are more vulnerable to cognitive decline compared to individuals showing a lower proinflammatory response. To test this hypothesis, we measured not only cognitive performance, but also the physiological response and biochemical determinants of metabolism and inflammation at baseline and after SD, but also in response to an acute social stressor (Tkacheenko & Dinges, 2018).