Passive heat stress reduces arterial carbon dioxide partial pressure (P(aCO2)) as reflected by 3 to 5 Torr reductions in end-tidal carbon dioxide tension (P(ETCO2)). Heat stress also reduces cerebrovascular conductance (CBVC) by up to 30%. While is a strong regulator of CBVC, it is unlikely that the relatively small change in during heating is solely responsible for the reductions in CBVC. This study tested the hypothesis that P(aCO2), referenced by P(ETCO2), is not the sole mechanism for reductions in CBVC during heat stress. Mean arterial blood pressure (MAP), P(ETCO2), middle cerebral artery blood velocity (MCA V(mean)), and calculated CBVC (MCA V(mean)/MAP) were assessed in seven healthy individuals, during three separate conditions performed sequentially: (1) normothemia, (2) control passive heat stress and (3) passive heat stress with P(ETCO2) clamped at the normothermic level (using a computer-controlled sequential gas delivery breathing circuit). MAP was similar in the three thermal conditions (P = 0.55). Control heat stress increased internal temperature approximately 1.3 degrees C, which resulted in decreases in P(ETCO2), MCA V(mean) and calculated CBVC (P < 0.001 for all variables). During heat stress + clamp conditions internal temperature remained similar to that during the control heat stress condition (P = 0.31). Heat stress + clamp successfully restored to the normothermic level (P = 0.99) and increased MCA V(mean) (P = 0.002) and CBVC (P = 0.008) relative to control heat stress. Despite restoration of P(ETCO2), MCA V(mean) (P = 0.005) and CBVC (P = 0.03) remained reduced relative to normothermia. These results indicate that heat stress-induced reductions in , as referenced by P(ETCO2), contribute to the decrease in MCA V(mean) and CBVC; however, other factors (e.g. perhaps elevated sympathetic nerve activity) are also involved in mediating this response.