l-carnitine is emerging as an item of interest for cardiovascular disease (CVD) prevention and treatment, but controversy exists. To examine the effectiveness and safety of l-carnitine, we assessed how genetically different levels of l-carnitine are associated with CVD risk and its risk factors. Given higher CVD incidence and l-carnitine in men, we also examined sex-specific associations. We used Mendelian randomization to obtain unconfounded estimates. Specifically, we used genetic variants to predict l-carnitine, and obtained their associations with coronary artery disease (CAD), ischemic stroke, heart failure, and atrial fibrillation, as well as CVD risk factors (type 2 diabetes, glucose, HbA1c, insulin, lipid profile, blood pressure and body mass index) in large consortia and established cohorts, as well as sex-specific association in the UK Biobank. We obtained the Wald estimates (genetic association with CVD and its risk factors divided by the genetic association with l-carnitine