Syncope from sustained orthostasis results from cerebral hypoperfusion associated with reductions in arterial pressure at the level of the brain (BP_MCA) and reductions in arterial CO₂ as reflected by end-tidal values (Pet_CO2). It was hypothesized that reductions in Pet_CO2 increase cerebrovascular tone before a drop in BP_MCA that ultimately leads to syncope. Twelve men (21–42 yr of age) completed an orthostatic tolerance test consisting of head-up tilt and progressive lower body negative pressure to presyncope, before and after completing 5 days of continuous head-down bed rest (HDBR). Cerebral blood velocity (CBFV), BP_MCA, and Pet_CO2 were continuously recorded throughout the test. Cerebrovascular indicators, cerebrovascular resistance, critical closing pressure (CrCP), and resistance area product (RAP), were calculated. Comparing from supine baseline to 6–10 min after the start of tilt, there were reductions in CBFV, Pet_CO2, BP_MCA, and CrCP, an increase in RAP, and no change in cerebrovascular resistance index. Over the final 15 min before syncope in the pre-HDBR tests, CBFV and CrCP were significantly related to changes in Pet_CO2 ( r = 0.69 ± 0.17 and r = 0.63 ± 0.20, respectively), and BP_MCA, which was not reduced until the last minute of the test, was correlated with a reduction in RAP ( r = 0.91 ± 0.09). Post-HDBR, tilt tolerance was markedly reduced, and changes in CBFV were dominated by a greater reduction in BP_MCA with no relationships to Pet_CO2. Therefore, pre-HDBR, changes in Pet_CO2 with orthostasis contributed to increases in cerebrovascular tone and reductions in CBFV during the progression toward syncope, whereas, after 5 days of HDBR, orthostatic responses were dominated by changes in BP_MCA.