Heat-related decreases in cerebral perfusion are partly the result of ventilatory-related reductions in arterial CO2 tension. Cerebral perfusion likely contributes to an individual's tolerance to a challenge like lower body negative pressure (LBNP). Thus increasing cerebral perfusion may prolong LBNP tolerance. This study tested the hypothesis that a hypercapnia-induced increase in cerebral perfusion improves LBNP tolerance in hyperthermic individuals. Eleven individuals (31 ± 7 yr; 75 ± 12 kg) underwent passive heat stress (increased intestinal temperature ∼1.3°C) followed by a progressive LBNP challenge to tolerance on two separate days (randomized). From 30 mmHg LBNP, subjects inhaled either (blinded) a hypercapnic gas mixture (5% CO2, 21% oxygen, balanced nitrogen) or room air (SHAM). LBNP tolerance was quantified via the cumulative stress index (CSI). Mean middle cerebral artery blood velocity (MCAvmean,) and end-tidal CO2 (PetCO2) were also measured. CO2 inhalation of 5% increased PetCO2 at ∼40 mmHg LBNP (by 16 ± 4 mmHg) and at LBNP tolerance (by 18 ± 5 mmHg) compared with SHAM (P < 0.01). Subsequently, MCAvmean was higher in the 5% CO2 trial during ∼40 mmHg LBNP (by 21 ± 12 cm/s, ∼31%) and at LBNP tolerance (by 18 ± 10 cm/s, ∼25%) relative to the SHAM (P < 0.01). However, hypercapnia-induced increases in MCAvmean did not alter LBNP tolerance (5% CO2 CSI: 339 ± 155 mmHg × min; SHAM CSI: 273 ± 158 mmHg × min; P = 0.26). These data indicate that inhaling a hypercapnic gas mixture increases cerebral perfusion during LBNP but does not improve LBNP tolerance when hyperthermic.