Abstract Background As a new obesity-related index, the weight-adjusted-waist index (WWI) appears to be a good predictor of cardiovascular disease (CVD) in East Asian populations. This study aimed to validate the association between WWI and CVD in United States (US) adults and also evaluate its relationships with the prevalence of specific CVDs. Methods The data were obtained from the 2009–2016 National Health and Nutrition Examination Survey. WWI was calculated as waist circumference divided by the square root of weight, and CVD was ascertained based on self-reported physician diagnoses. Multivariable logistic regression models and subgroup analyses were performed to evaluate the association between WWI and CVD. Results A total of 21,040 participants were included. There was a positive linear relationship between WWI and the odds of CVD (P = 0.310). After adjusting for all covariates, each unit of increased WWI was associated with 48% increased risk of CVD (odds ratio [OR]: 1.48, 95% confidence interval [CI]: 1.25–1.74). Moreover, compared with the lowest quintile (