BACKGROUND: The systemic immune-inflammation index (SII) is a simple parameter that has been used to predict adverse outcomes in different clinical settings. The prognostic value of SII, an innovative biomarker of inflammation, in non-valvular atrial fibrillation (NVAF) patients has not been assessed. The aim of this study was to evaluate the prognostic value of SII in NVAF patients who were under direct oral anticoagulant (DOAC) medication. METHODS: A total of 467 patients with NVAF treated with DOACs from 2018 to 2021 were retrospectively enrolled in this cohort study. Demographics, medication, and outcome data were collected for each patient. SII was calculated from complete blood counts as the ratio of neutrophil-to-lymphocyte count multiplied by the platelet count. The primary outcome was major adverse events (MAEs), which include major bleeding, stroke, and death. RESULTS: Logistic regression analyses showed that the SII score was an important predictor of outcomes in NVAF patients. CONCLUSION: The SII may be a successful, non-invasive, and cost-effective parameter for predicting bleeding and stroke in patients with NVAF. It may be used as a useful risk stratification tool for these patients.