(1) Background: The Systemic immune-inflammatory index (SII) has been proven to be an effective biomarker of human immune and inflammatory levels and has prognostic significance for most diseases. Handgrip strength (HGS) is a simple and low-cost strength measurement method, which is not only highly correlated with overall muscle strength but also accurately and reliably predicts the risk of multiple chronic diseases and mortality; (2) Purpose: Association between HGS and the SII is unclear. The purpose of this study was to investigate the association between HGS and the SII in American adults; (3) Methods: We used the data from the 2011-2012 and 2013-2014 cycles of the National Health and Nutrition Examination Survey (NHANES), involving a total of 8232 American adults (aged 18-80 years). The SII was calculated as the Platelet count × Neutrophil count/Lymphocyte count; HGS was recorded as the ratio of the sum of the highest grip-strength values of each hand to body mass index taken as the relative grip strength. A weighted generalized linear regression model and analysis of restricted cubic spline regression, adjusted for confounding factors, were used in this study to assess associations between HGS and the SII in American adults; (4) Results: There was a negative correlation between the HGS and the SII of different sexes (p < 0.05), and there was a significant negative nonlinear relationship between the HGS and the SII in males (p for nonlinear = 0.0035), and the SII showed a downward trend with the increase in the HGS in males (Q2: β = -61.03, p = 0.01; Q3: β = -61.28, p = 0.04, Q4: β = -64.36, p = 0.03, p for trend = 0.04), when the HGS exceeds 3.16, with the HGS increasing, the downward trend of increasing the SII slowed down. The nonlinear relationship between the HGS and the SII in females was not significant (p for nonlinear = 0.1011), and the SII showed a linear downward trend with the increase in the HGS (Q2: β = -24.91, p = 0.25; Q3: β = -62.01, p = 0.03, Q4: β = -74.94, p = 0.03, p for trend = 0.01); (5) Conclusions: HGS is inversely and independently associated with SII levels, and although the limited cubic spline regression analysis showed gender differences, the overall trend of the HGS and the SII in different genders was consistent, with both showing that the SII decreased with increasing the HGS. In addition, HGS has high general applicability based on its ease of measurement; it is possible to understand one's own grip-strength level through routine grip-strength tests, and to make preliminary predictions on the current level of immunity and inflammation in the body.

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