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• Elevated SII levels linked to higher frailty and mortality risk. • U-shaped relationship found between SII levels and mortality. • Critical SII thresholds identified for all-cause and cancer-related mortality. • Maintaining low SII levels may reduce frailty and mortality risk. Frailty is a state of heightened vulnerability to stress, whether from within the body or external factors. We aim to assess the prognostic value of the Systemic Immune-Inflammation Index (SII) in middle-aged and older frail adults. We used data from the 2003–2018 National Health and Nutrition Examination Survey (NHANES) linked to the 2019 National Death Index (NDI) to study mortality. Cox proportional hazards model and two-piecewise Cox proportional hazards model were used to elucidate the nonlinear relationship between SII level and mortality. Our study included 7,446 frail patients (mean age 65.6) with 2,524 deaths (726 from cardiovascular disease and 458 from cancer) over 49,565 person-years. Elevated SII levels were associated with an increased risk of all-cause, cardiovascular disease (CVD)-related and cancer-related mortality, even after adjusting for potential confounders (adjusted HR (95 % CI) = 1.35 (1.25, 1.46), 1.42 (1.22, 1.65) and 1.26 (1.05, 1.51), respectively). Moreover, a U-shaped correlation was discerned between SII levels and the risks of all-cause and cancer-related mortality, with respective thresholds identified at 334.96 and 348.28. Our findings reveal SII levels positively correlate with frailty, all-cause mortality, CVD-related mortality, and cancer-related mortality in middle-aged and elderly frail individuals in the U.S. The critical thresholds for SII index were 334.96 for all-cause mortality and 348.28 for cancer-related mortality. This study underscores the potential benefits of maintaining a certain low level of SII to effectively mitigate the incidence of frailty and mortality among frail patients. [ABSTRACT FROM AUTHOR]