Introduction: In various acute conditions, including acute ischemic stroke (AIS), a stress response occurs, often leading to elevated blood glucose (BG) levels, the so-called stress hyperglycemia (SH). Its adequate assessment would be particularly useful in clinical practice, both for identifying high-risk patients and for therapeutic behavior.Aim: The aim of this article is to analyze cortisol levels and glycated hemoglobin (HbA1c)-based glycemic variables as markers for assessment of stress response in AIS and to look for an association with adverse clinical outcome.Materials and Methods: A cross-sectional study including 114 patients with AIS, stratified according to BG at admission (admBG) and the presence of diabetes mellitus (DM)—with normoglycemia, SH, previously and newly diagnosed type 2 DM was conducted. Serum cortisol levels, as well as HbA1c-based glycemic variables were evaluated according to the severity of stroke (assessed by National Institutes of Health Stroke Scale, NIHSS score) and the prevalence of fatal outcome.Results: The SH group demonstrated the greatest AIS severity at admission, accompanied by the highest serum cortisol levels, with a significant difference in both indicators compared to the NG group (NIHSS 15.33 ± 8.39 vs.10.63 ± 6.12, p = 0.016; serum cortisol 1039 ± 668 vs. 701.7 ± 380.8 p = 0.046). Furthermore, in patients with a fatal outcome compared to survivors, we observed significantly more severe AIS (NIHSS 15.93 ± 5.31 vs. 9.72 ± 6.31, p < 0.0001), as well as higher serum cortisol levels (1060 ± 572.1 vs. 610.5 ± 284.8, p < 0.0001). In contrast to admBG, HbA1c-based glycemic variables demonstrated the highest values in the SH group. Both cortisol and glycemic variables, but not admBG, showed positive correlation with AIS severity at admission.Conclusion: Serum cortisol levels could be useful in assessing the severity of AIS and identifying high-risk patients. HbA1c-based glycemic variables are better determinants of stress response than absolute BG values
