BACKGROUND: Early age at menarche (AAM) has been associated with a higher risk of carotid artery intima-media thickness (cIMT), an indicator of subclinical vascular disease, albeit the mechanisms underlying this association remain elusive. A better understanding of the relationship between AAM, modifiable cardiometabolic risk factors, and subclinical atherosclerosis may contribute to improved primary prevention and cardiovascular disease treatment. We aimed to investigate the putative causal role of AAM on cIMT, and to identify and quantify the potentially mediatory effects of cardiometabolic risk factors underlying this relationship. METHODS AND RESULTS: We conducted linkage disequilibrium score regression analyses between our exposure of interest, AAM, our outcome of interest, cIMT and potential mediators of the AAM-cIMT association to gauge cross-trait genetic overlap. We considered as mediators the modifiable anthropometric risk factors body mass index (BMI), systolic blood pressure (SBP), lipid traits (total cholesterol, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol), and glycemic traits (fasting glucose). We then leveraged the paradigm of Mendelian randomization to infer causality between AAM and cIMT, and to identify whether cardiometabolic risk factors served as potential mediators of this effect. Our analyses showed that genetically predicted AAM was inversely associated with cIMT, BMI, SBP, and triglycerides, and positively associated with high-density lipoprotein, low-density lipoprotein, and total cholesterol. We showed that the effect of genetically predicted AAM on cIMT may be partially mediated through BMI (20.1% [95% CI, 1.4% to 38.9%]) and SBP (13.5% [95% CI, 0.5%-26.6%]). Our cluster-specific Mendelian randomization revealed heterogeneous causal effect estimates of age at menarche on BMI and SBP. CONCLUSIONS: We highlight supporting evidence for a potential causal association between earlier AAM and cIMT, and almost one third of the effect of AAM on cIMT may be mediated by BMI and SBP. Early intervention aimed at lowering BMI and hypertension may be beneficial in reducing the risk of developing subclinical atherosclerosis due to earlier age at menarche.