Clinical TCD assessment of cerebral vasomotor reactivity (CVMR) uses linear regression of cerebral blood flow velocity (CBFV) versus end-tidal CO₂ (P_ETCO2) under steady-state conditions. However, the CBF-P_ETCO2 relationship is nonlinear, even for moderate changes in CO₂. Moreover, CBF is increased by increases in arterial blood pressure (ABP) during hypercapnia. We used a modified rebreathing protocol to estimate CVMR during breath-by-breath changes in P_ETCO2. Ten healthy subjects (6 men) performed 15 s of hyperventilation followed by 5 min of rebreathing, with supplemental O₂ to maintain arterial oxygen saturation constant. To minimize effects of ABP on estimation of CVMR, cerebrovascular conductance index (CVCi) was calculated. The CBF/CVCi-P_ETCO2 relationships were quantified using both linear and logistic regression. In three subjects, muscle nerve sympathetic activity (MSNA) was recorded. Robust changes occurred in P_ETCO2 (20 to 61 mmHg), CBFV (-44 to +104 % of baseline), CVCi (-39 to +64 %) and ABP (-19 to +23 %), (all p < 0.01). MSNA increased by 446 % during hypercapnia. The linear slope of CVCi vs. P_ETCO2 was less steep than CBFV (3 vs. 5 %^.mmHg^-1, p = 0.01). Logistic regression of CBF-P_ETCO2 (r2, 0.97) and CVCi-P_ETCO2 (r2, 0.93) was superior to linear regression (r², 0.91; r², 0.85; p = 0.01). CVMR was maximal (6-8 % mmHg^-1) in the range 40-50 mmHg P_ETCO2. Cerebrovascular responses to changes in P_ETCO2 can be described by a logistic function. Quantification of the CVCi-P_ETCO2 relationship minimizes effects of ABP on the estimation of CVMR.