BACKGROUND: Systemic nutrition and inflammation status is recognized for its influence on cancer survival, yet its role in perioperative outcomes remains poorly defined. This study aimed to refine the assessment of systemic nutrition and inflammation status in non-small cell lung cancer (NSCLC) patients and to elucidate its impact on perioperative outcomes. METHODS: All patients underwent video-assisted thoracoscopic lobectomy, with their nutrition and inflammation status assessed based on preoperative blood tests. The development cohort, comprising 1497 NSCLC patients from two centers, evaluated the predictive value of systemic nutrition/inflammation indicators for perioperative endpoints and formulated the systemic nutrition-inflammation index (SNII). The tertiles of SNII were used to classify the nutrition/inflammation risk as high (<
15.6), moderate (15.6-23.1), and low (>
23.1). An external validation cohort of 505 NSCLC patients was utilized to confirm the effectiveness of SNII in guiding perioperative management. RESULTS: In the development cohort, the SNII tool, calculated as the product of total cholesterol and total lymphocytes divided by total monocytes, demonstrated a stronger correlation with perioperative outcomes compared to 11 existing nutrition/inflammation indicators. A low SNII score, indicative of high nutrition/inflammation risk, was independently predictive of increased complication incidence and severity, as well as prolonged chest tube duration and hospital stay. These findings were corroborated in the validation cohort. Upon combining the development and validation cohorts, the superiority of the SNII in predicting perioperative outcomes was further confirmed over the existing nutrition/inflammation indicators. Additionally, comprehensive subgroup analyses revealed the moderately variable efficacy of SNII across different patient populations. CONCLUSIONS: This study developed and validated the SNII as a tool for identifying systemic nutrition and inflammation risk, which can enhance perioperative managements in NSCLC patients. Patients identified with high risk may benefit from prehabilitation and intensive treatments, highlighting the need for further research.