Cognitive and/or sensorimotor stimulation of the brain induce increases in cerebral blood flow that are usually associated with increased metabolic demand. We tested the hypothesis that changes in arterial blood pressure (ABP) and arterial carbon dioxide tension (pCO₂) also take place during brain activation protocols designed to induce hemispheric lateralization, leading to a pressure-autoregulatory response in addition to the metabolic driven changes usually assumed by brain stimulation paradigms. Continuous recordings of CBFV (bilateral, middle cerebral artery (MCA)), ABP, ECG and end-tidal CO₂ (EtCO₂) were performed in 15 right-handed healthy subjects (aged 21-43 years), in the seated position, at rest and during 10 repeated presentations of a word generation and a constructional puzzle paradigm that are known to induce differential cortical activation. Derived variables included heart rate, cerebrovascular resistance, critical closing pressure, resistance-area product, and the difference between the right and left MCA recordings (CBFV_R-L). No adaptation of the CBFV_R-L difference was detected for the repeated presentation of 10 activation tasks, for either paradigm. During activation with the word generation tasks, CBFV changed by (mean ± SD) 9.0 ±3.7 % (right MCA, p=0.0007) and 12.3 ± 7.6 % (left MCA, p=0.0007), ABP by 7.7 ± 6.0 mmHg (p=0.0007), heart rate by 7.1 ± 5.3 beats/min (p=0.0008) and end-tidal CO₂ by -2.32 ± 2.23 mmHg (p=0.002). The corresponding changes for the puzzle paradigm were CBFV (right MCA) 13.9 ± 6.6 % (p=0.0007), CBFV (left MCA) 11.5 ± 6.2 % (p=0.0007), ABP 7.1 ± 8.4 mmHg (p=0.0054), heart rate 7.9 ± 4.6 beats/min (p=0.0008) and end-tidal CO₂ -2.42 ± 2.59 mmHg (p=0.001). The word paradigm led to greater left hemispheric dominance than the right hemispheric dominance observed with the puzzle paradigm (p= 0.004). We concluded that significant changes in ABP and EtCO₂ levels occur during brain activation protocols and contribute to the evoked change in CBFV. A pressure-autoregulatory response can be observed in addition to the hemodynamic changes induced by increases in metabolic demand. Simultaneous changes in pCO₂ and heart rate add to the complexity of the response indicating the need for more detailed modeling and better understanding of brain activation paradigms.