AbstractAcute exposure to carbon dioxide (CO₂) concentrations below those found on the International Space Station are reported to deteriorate complex decision-making. Effective decision-making is critical to human spaceflight, especially during an emergency response. Therefore, effects of acutely elevated CO₂ on decision-making competency and various cognitive domains were assessed in astronaut-like subjects by the Strategic Management Simulation (SMS) and Cognition test batteries. The double-blind cross-over study included 22 participants at the Johnson Space Center randomly assigned to one of four groups. Each group was exposed to a different sequence of four concentrations of CO₂ (600, 1200, 2500, 5000 ppm). Subjects performed Cognition before entering the chamber, 15 min and 2.5 h after entering the chamber, and 15 min after exiting the chamber. The SMS was administered 30 min after subjects entered the chamber. There were no clear dose–response patterns for performance on either SMS or Cognition. Performance on most SMS measures and aggregate speed, accuracy, and efficiency scores across Cognition tests were lower at 1200 ppm than at baseline (600 ppm); however, at higher CO₂ concentrations performance was similar to or exceeded baseline for most measures. These outcomes, which conflict with those of other studies, likely indicate differing characteristics of the various subject populations and differences in the aggregation of unrecognized stressors, in addition to CO₂, are responsible for disparate outcomes among studies. Studies with longer exposure durations are needed to verify that cognitive impairment does not develop over time in crew-like subjects.