Modified Radical Mastectomy (MRM) may induce a systemic inflammatory response that can affect postoperative recovery in patients with breast cancer. The Systemic Immune-Inflammatory Index (SII) is an inflammatory biomarker calculated from platelet, neutrophil, and lymphocyte counts. This study aimed to compare postoperative changes in SII among breast cancer patients undergoing MRM who received epidural anesthesia and general anesthesia at Ibnu Sina YW-UMI Hospital. This retrospective analytical observational study used a comparative approach based on medical records of breast cancer patients who underwent MRM between January and December 2024. SII was calculated using the formula (platelet count × neutrophil count)/lymphocyte count, while the change in SII was defined consistently as the postoperative SII minus the preoperative SII (?SII = SII postoperative ? SII preoperative). Statistical analyses included the paired t-test, Wilcoxon test, and Mann–Whitney test according to data distribution. A total of 36 patients were included, comprising 10 patients who received epidural anesthesia and 26 who received general anesthesia. In the epidural group, the mean SII decreased from 839.04 preoperatively to 477.04 postoperatively. In contrast, the mean SII in the general anesthesia group increased from 742.28 to 1,487.24. The comparison of postoperative SII changes between the two anesthesia groups showed a statistically significant difference (p<0.001). These findings indicate different postoperative SII dynamics following MRM between patients receiving epidural and general anesthesia. However, the findings should be interpreted cautiously because of the retrospective design, unequal group sizes, and potential confounding factors that were not fully controlled. Further prospective studies with standardized postoperative blood sampling and adjustment for relevant perioperative confounders are warranted.