OBJECTIVE Stable xenon-enhanced CT ((s)Xe/CT) has gained wide acceptance in the assessment of regional cerebral blood flow (rCBF) in patients with intracranial abnormalities. The aim of this study was to test whether the contrast medium (ie, (s)Xe) itself directly induces relevant changes in rCBF, thereby distorting any valid determination of cerebral perfusion by using (s)Xe/CT. METHODS To characterize the degree and temporal dynamics of (s)Xe-induced flow activation, a thermal diffusion (TD)-based microprobe was placed subcortically into the frontal lobe on either hemisphere to assess rCBF (TD-rCBF) continuously in 23 patients (mean age, 55 +/- 18 years) with severe intracranial insult who were undergoing (s)Xe/CT. RESULTS In 35, the (s)Xe/CT studies TD-rCBF rose from 25 +/- 17 mL/100 g per minute (range, 5-42 mL/100 g per minute) before (s)Xe administration to 28 +/- 21 mL/100 g per minute (range, 6-46 mL/100 g per minute) after arterial (s)Xe saturation was reached. Analysis of the flow activation curve showed a logarithmic shape with an increase in TD-rCBF between 3% and 7% within the first 76 seconds of (s)Xe wash-in (12% after 190 seconds) and showed no further augmentation until the end of the blood flow study. CONCLUSIONS The observed (s)Xe-induced rCBF activation, which showed significant inter- and intraindividual variability, might lead to overestimation of rCBF in patients with severe intracranial insult. The obtained flow activation curve provides essential information that may allow subsequent refinement of the methodology, aiming to further minimize the influence of (s)Xe-induced rCBF activation on rCBF calculations when using (s)Xe/CT technology.