<p>Craniotomy remains a relatively high-risk procedure, yet there is a lack of biomarkers to predict poor postoperative prognosis in brain tumor patients. To assess the efficacy of the Systemic Immune-Inflammation Index (SII) as a prognostic biomarker for patients with brain tumors undergoing craniotomy procedures. Utilizing historical patient data, this research encompassed individuals with brain tumors who were subjected to craniotomy procedures from January 2011 through March 2021. The principal metric of interest was the mortality rate within 30 days post-operation. SII was derived from pre-surgical complete blood counts. Receiver Operating Characteristic (ROC) curve analysis was utilized to determine the threshold value of the SII capable of predicting 30-day postoperative mortality. Following this, both univariate and multivariate logistic regression analyses were performed to identify factors associated with mortality and clinical complications related to the SII. A total of 10,202 patients were included in the study. The optimal cut-off value for the SII in predicting 30-day mortality was determined to be 620.72, based on the ROC curve and Youden Index. Elevated preoperative SII levels were significantly associated with higher 30-day mortality (adjusted OR 2.31, 95% CI 1.64–3.24). Additionally, a higher SII was also linked to increased long-term mortality (adjusted OR 2.08, 95% CI 1.83–2.36). For brain tumor patients underwent craniotomy, a high preoperative SII (≥ 620.72) is an independent predictor of postoperative mortality and complications. SII is a simple and inexpensive inflammatory biomarker that may be useful in perioperative prognostication for craniotomies patients.</p>