Background. Major surgery is associated with a stress response. Te aim of this study was to compare the effects of isofurane or propofol, both supplemented with remifentanil, on the glucose, cortisol and insulin-based stress responses prospectively. Methods. Forty patients undergoing craniotomy randomly received either 1% isofurane (Group I, N.=20) or pro-pofol 6 mg kg h -1 (Group P, N.=20) during remifentanil-based (0.125 μg kg min -1) anesthesia. Blood glucose was recorded preoperatively, after induction, intubation and pin placement, before and after skin incision, craniotomy, dura incision, 15 th, 30 th, 60 th, 90 th, 120 th, 150 th, 180 th min post-dura incision, following dura and skin closure, extubation and at the 1 st and 24 th postoperative hours. Insulin and cortisol were measured preoperatively, after intubation, dura incision, at the 60 th min, extubation and at the 1 st and 24 th hour postoperatively. Te glucose/insulin ratio and glycemic stress index were calculated after all the measurements were obtained. Results. Patient characteristics were comparable in both groups. Blood glucose significantly decreased after induction in comparison to the baseline value in both groups. Blood glucose was significantly higher in Group I than Group P before skin incision, after craniotomy and dura incision and at all measurement time points after the 60th minute following dura incision. There was a significant alteration with time in insulin values in both groups and the insulin values at the 60th min were significantly lower in Group I than in Group P. Tere was not any difference in the inter-group analysis of cortisol; however, there was a significant change over time in the insulin values in both groups. There was no difference in the intra-group glucose/insulin ratio, however, there was a significant difference between groups at the 60th min and at extubation. Te Glycemic Stress Index was comparable between groups (Group I vs. Group P: 2.48±1.15 vs. 2.15±0.86, P=0.465). Conclusion. Isofurane and propofol, both combined with remifentanil, provided clinically comparable cortisol and insulin responses to surgery in craniotomy operations, whereas propofol attenuated the increase in plasma blood glucose.