Background Legal performance-enhancing substances (PES), such as creatine, are commonly used by adolescents and young adults. As PES are mostly unregulated by the US Food and Drug Administration, there has been limited empirical attention devoted to examining their longterm safety and health outcomes. Preliminary studies have demonstrated associations between PES use and severe medical events, including hospitalizations and death. PES could be linked to cardiovascular disease (CVD), the most common cause of mortality in the US, by altering the myocardium, vasculature, or metabolism. The objective of this study was to examine prospective associations between the use of legal PES in young adulthood and CVD risk factors at seven-year follow-up. Materials and methods Nationally representative longitudinal cohort data from the National Longitudinal Study of Adolescent to Adult Health, Waves III (2001-2002) and IV (2008), were analyzed. Regression models determined the prospective association between the use of legal PES (e.g. creatine monohydrate) and CVD risk factors (e.g. body mass index, diabetes, hypertension, hyperlipidemia), adjusting for relevant covariates. Results Among the diverse sample of 11, 996 male and female participants, no significant differences by PES use in body mass index, diabetes, hypertension, or hyperlipidemia were noted at Wave III. In unadjusted comparisons, legal PES users (versus non-users) were more likely to be White, be male, be college educated, drink alcohol, and engage in weightlifting, exercise, individual sports, team sports, and other strength training. There were no significant prospective associations between legal PES use at Wave III and body mass index, hemoglobin A1c, systolic and diastolic blood pressure, and cholesterol (total, HDL, LDL, triglycerides) deciles at seven-year follow-up (Wave IV), adjusting for demographics, health behaviors, and Wave III CVD risk factors. Similarly, there were no significant prospective associations between legal PES use and diabetes, hypertension, or hyperlipidemia based on objective measures or self-reported medications and diagnoses, adjusting for demographics, health behaviors, and Wave III CVD risk. Conclusions We do not find evidence for a prospective association between legal PES use and CVD risk factors in young adults over seven years of follow-up, including BMI, diabetes, hypertension, or hyperlipidemia. It should be noted that legal PES use was operationalized dichotomously and as one broad category, which did not account for frequency, amount, or duration of use. Given the lack of regulation and clinical trials data, observational studies can provide much needed data to inform the safety and long-term health associations of legal PES use and, in turn, inform clinical guidance and policy.