Objective <p>To investigate the changes in the aggregative index of systemic inflammation (AISI) in patients with type 2 diabetes mellitus (T2DM) complicated by lower extremity peripheral arterial disease (PAD), and to evaluate its association with and discriminatory efficacy for disease severity and amputation risk.</p> Methods <p>This cross-sectional study enrolled 265 T2DM patients who were hospitalized at Binhai County People's Hospital between January 2024 and September 2025. Based on the diagnostic criteria, the patients were divided into a T2DM-only group (non-PAD group, <i>n</i> = 125) and a T2DM with PAD group (PAD group, <i>n</i> = 140). To further assess disease severity, patients in the PAD group were subdivided into a chronic limb-threatening ischemia (CLTI) subgroup (<i>n</i> = 82) and a non-CLTI subgroup (<i>n</i> = 58). Clinical data and laboratory indicators were collected and compared between the groups. Least absolute shrinkage and selection operator (LASSO) regression combined with ten-fold cross-validation was used to screen core associated variables for the risk of PAD and amputation in T2DM patients. The discriminative model's performance, including its discriminative ability, calibration, and clinical utility, were systematically evaluated using receiver operating characteristic (ROC) curves, calibration plots, and decision curve analysis (DCA).</p> Results <p>The AISI levels were significantly higher in the PAD group as compared to the non-PAD group (<i>P</i> &lt; 0.05). Furthermore, AISI levels were significantly elevated in the CLTI subgroup relative to the non-CLTI subgroup (<i>P</i> &lt; 0.05). Spearman’s correlation analysis revealed that AISI was positively correlated with white blood cell count (WBC), neutrophil count (NEU), monocyte count (MON), platelet count (PLT), and D-dimer (<i>P</i> &lt; 0.05), while it was negatively correlated with bilateral ankle-brachial index (ABI) and lymphocyte count (LYM) (<i>P</i> &lt; 0.05). LASSO regression identified key factors associated with T2DM complicated by PAD, including D-dimer (OR = 6.819), MON (OR = 4.758), Duration of diabetes (OR = 1.417), glycated hemoglobin (HbA1c, OR = 0.736), age, and systolic blood pressure (SBP, OR = 1.055). A discriminative model constructed based on these variables demonstrated excellent performance, with area under the curve (AUC) values of 0.960 in the training set and 0.913 in the test set. For amputation risk discrimination, LASSO regression identified four core variables: AISI, MON, WBC, and D-dimer. AISI emerged as the primary associated factor (absolute coefficient = 2.642; multivariable logistic regression OR = 46.735). This model showed outstanding discriminative ability, with AUCs of 0.966 in the training set and 0.905 in the test set.</p> <p>The calibration plot indicated good consistency between the model-estimated probabilities and observed outcomes, and DCA confirmed significant net clinical benefit across a wide range of threshold probabilities.</p> Conclusion <p>AISI was significantly elevated in T2DM-PAD patients and independently associated with disease severity (CLTI) and amputation risk. As a comprehensive inflammatory marker derived from routine blood tests, AISI demonstrates promising clinical potential for assessing disease severity and identifying high-risk individuals among T2DM-PAD patients.</p>