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Aims Methods Results Conclusions The relationship between α‐Klotho (αK) and mortality is controversial and has not been examined in a large, diverse cohort. We investigated the association between serum αK protein levels with all‐cause and cause‐specific mortality in a cohort representative of the US population.We used National Health and Nutrition Examination Survey (NHANES) data from 2007 to 2016. A nonlinear association between mortality and αK levels as a quadratic variable were examined using Cox proportional hazard models and competing risk models. Multivariable models were adjusted for age, gender, race, hypertension, diabetes, smoking, alcohol use, physical activity, body mass index (BMI), serum cholesterol, estimated glomerular filtration rate, highest educational status attained and family income to poverty threshold ratio.Of the 13 749 participants, 1569 (11%) died, 7092 (52%) were female, and 5918 (43%) were Caucasian. The mean (SD) of age was 58 (11) years, BMI 29.7 (6.7) kg/m2, and αK was 0.85 (0.31) ng/mL. In the adjusted Cox proportional hazards model with quadratic αK, we found a U‐shaped relationship between all‐cause mortality and αK levels (continuous αK hazard ratio [HR] = 0.56, 95% confidence interval [CI]: 0.37, 0.85; P = .007; squared‐αK HR = 1.25, 95% CI: 1.11, 1.41; P < 0.001). A similar U‐shaped relationship was noted between αK and cancer mortality in the adjusted Cox proportional hazards model (continuous αK HR = 0.45, 95% CI: 0.19, 1.06; P = 0.07; squared αK HR = 1.32, 95% CI: 1.07, 1.61; P = 0.009). No relationship was present with cardiovascular or other‐cause mortality.In this large diverse cohort, we report a U‐shaped relationship between αK with all‐cause and cancer mortality. Further research to elucidate the underlying biological mechanism of these relationships is needed. [ABSTRACT FROM AUTHOR]