ObjectiveAccumulating experimental evidence has identified the beneficial effects of the anti-aging protein, serum soluble alpha-Klotho, on longevity, and the cardiovascular system. Although a previous study has revealed the predictive value of alpha-Klotho on total cardiovascular disease (CVD), the associations between alpha-Klotho and specific CVDs, including congestive heart failure (CHF), coronary heart disease (CHD), myocardial infarction (MI), and stroke, remains to be fully elucidated in humans. MethodsFor 8,615 adults in the 2007 to 2016 National Health and Nutrition Examination Survey, stratified multivariable logistic regression models, restricted cubic spline curves, and subgroup analyses were used to evaluate the associations between alpha-Klotho and the four specific CVDs. ResultsIn the quartile analyses, compared to those in the highest quartile, participants in the lowest level of alpha-Klotho were significantly associated with CHF [odds ratio (OR) = 1.46, 95% CI: 1.09-1.97] and MI (1.33, 1.02-1.74), which was not the case for CHD (1.12, 0.91-1.38) or stroke (0.96, 0.73-1.25). Each unit increment in the ln-transformed alpha-Klotho concentrations was only positively associated with a 38 and 24% reduction in the prevalence of CHF and MI, respectively. Restricted cubic spline curves indicated that the alpha-Klotho was correlated with CHF and MI in linear-inverse relationships. ConclusionThe present findings suggested that the serum soluble alpha-Klotho is significantly associated with the prevalence of CHF and MI. To better determine whether alpha-Klotho is a specific biomarker of CVD, particularly for CHD and stroke, further research in humans is needed.