Purpose. Acute ischemic stroke (AIS) is a devastating disease and remains the leading cause of death and disability. This retrospective study aims to investigate associations between systemic immune-inflammation index (SII) and all-cause mortality in patients with AIS. Patients and Methods. We used the data from Medical Information Mart for Intensive Care IV. A total of 1,181 patients with acute ischemic stroke (AIS) were included. Systemic immune-inflammation index (SII) was calculated as platelet count (/L) × neutrophil count (/L)/lymphocyte count (/L). The main outcomes were 30-day all-cause mortality. The association between SII with mortality was evaluated using the Cox proportional hazards regression model. Results. After adjusting for potential covariates, the highest quartiles of SII versus the lowest quartiles of SII, the HR was 2.74 (CI 1.79–4.19, P < 0.001 ). Log-transformed SII was significantly associated with 30-day all-cause mortality (HR 2.44; CI 1.72–3.46, P < 0.001 ). Furthermore, we found that there is a nearly linear relationship ( P = 0.265 ) between logarithmic transformed SII with all-cause mortality. Conclusion. Elevated SII of patients with acute ischemic stroke increased the risk of 30-day all-cause mortality. SII may serve as a useful marker to elucidate the role of thrombocytosis, inflammation, and immunity interaction in the development of AIS.