Background: To investigate the influence of systemic inflammation on dynamic cerebral autoregulation and vascular tone during experimental human endotoxemia and sepsis. Methods: Healthy volunteers received 3 h continuous infusion of LPS (c-LPS, 4 ng/kg, n = 11, Clinicaltrials.gov NCT02922673) or a bolus of LPS (b-LPS, 2 ng/kg, n = 8, Clinicaltrials.gov NCT02675868) and 10 sepsis patients were studied. Mean arterial pressure (MAP) and cerebral blood flow velocity (CBFV) were monitored simultaneously. Cerebral autoregulation was analysed by transfer function analysis (TFA). Critical closing pressure (CrCP) was estimated as a measure of cerebral vascular tone. Results: c-LPS resulted in a more pronounced and prolonged plasma cytokine response compared with b-LPS. MAP decreased from 89 ± 3 to... 75 ± 2 mmHg (p < 0.05) and from 91 ± 2 to 77 ± 3 mmHg (p < 0.001) in the c-LPS and b-LPS groups, respectively. MAP in sepsis patients was 65 ± 4 mmHg. TFA in both LPS groups showed no significant changes over time in coherence, gain and phase. Phase in sepsis patients was lower compared with both LPS groups (7 (2 to 33) [median (interquartile range)] in sepsis versus 57 (36 to 74) in the c-LPS (p = 0.02) and 53 (43 to 64) degrees in the b-LPS group (p = 0.01)). CrCP decreased from 49 ± 2 to 41 ± 2 mmHg (p = 0.16) in the c-LPS and from 50 ± 2 to 42 ± 2 mmHg in the b-LPS group (p < 0.01), and was 36 ± 2 mmHg in sepsis patients. Conclusions: Dynamic cerebral autoregulation is impaired in sepsis patients, but remains intact during experimental human endotoxemia. CrCP decreased during endotoxemia and was low in sepsis, reflecting decreased vascular tone. This indicates activation of a cerebrovascular adaptive process, also during experimental endotoxemia with intact cerebral autoregulation.