BackgroundThe systemic immune-inflammation index (SII), as a novel inflammatory biomarker, has recently attracted attention in cardiovascular disease research. However, the relationship between SII and risk of lower extremity deep venous thrombosis (LEDVT) remains unclear to date. Thus, this study aimed to explore the association in a large sample over a 10-year period (2012–2022).MethodsAll hospitalized patients undergoing lower extremity compression ultrasonography (CUS) examination were consecutively screened by searching our hospital information system database. The receiver operating characteristic (ROC) curve analysis was used to identify the optimal cut-off value for high and low SII group. Multivariate logistic regression analyses were performed to investigate the relationship between SII and LEDVT risk. Propensity score matching (PSM), subgroup and sensitivity analyses were also conducted. Moreover, restricted cubic spline (RCS) regression and two-piecewise linear regression models were used to assess the dose-response relationship between natural log transformed SII [ln(SII)] and risk of LEDVT.ResultsA total of 16,725 consecutive hospitalized patients were included, and 1,962 LEDVT events occurred. After adjusting for confounding factors, patients in the high SII group (≥ 574.2 × 109/L) showed a 1.740-fold risk of LEDVT (95%CI: 1.546–1.959,P< 0.001), and elevated ln(SII) was associated with a 36.1% increased risk of LEDVT (95%CI: 1.278–1.449,P< 0.001). PSM, subgroup and sensitivity analyses confirmed the robustness of the association. A non-linear relationship was observed (Pnon−linear< 0.001), with a threshold value of 5.6 × 109/L for all LEDVT events. Above the threshold, each unit increase in ln(SII) had a 1.369-fold higher risk of LEDVT (95%CI: 1.271–1.475,P< 0.001). The association also existed in both distal and proximal LEDVT.ConclusionElevated SII is significantly associated with an increased risk of LEDVT in hospitalized patients. Additionally, the association is non-linear and exhibit a threshold effect.