Abstract Background One may add monosodium glutamate (MSG) to food for its flavour-enhancing properties. However, its implication in long-term cardiovascular health is uncertain due to a lack of precise epidemiological evidence. This study aimed to investigate the associations between food additive glutamate exposures and cardiovascular disease (CVD) risk, including cerebrovascular disease (CVA) and coronary heart disease (CHD) risks in a large prospective cohort of French adults. Methods Participants (n = 108,932, 79.3% women, mean age=42.4 years, SD = 14.5) were 15 years old and above from the French NutriNet-Santé prospective cohort (2009-2023). We assessed dietary intakes using repeated 24h-dietary records and exposure to food additive glutamate using food composition databases and laboratory assays. We characterised associations between cumulative time-dependent continuous exposures to total glutamate, natural glutamic acid, MSG and risk of CVD, CVA, and CHD using multivariable proportional hazards Cox models adjusted for known risk factors for standardised increments of glutamate intake. Results During follow-up (median 7.92 years), 2397, 1113, and 1284 participants were diagnosed with CVD, CVA, and CHD respectively. Higher intakes of naturally occurring glutamic acid (HR per 3000 mg/d increment=1.08, 95% CI [1.01-1.16], p-value=0.03), food additive MSG (HR per 200 mg/d increment=1.05, 95% CI [1.01-1.09], p-value=0.03), and total glutamate (HR per 3000 mg/d increment=1.09, 95% CI [1.01-1.17], p-value=0.02) were associated with higher risks of CHD (p-value for non-linearity>0.6). Conclusions This large prospective cohort study revealed positive associations between exposure to the widely used glutamate food additives, especially MSG (E621) and CVD, CVA, and CHD risks. Key messages • This large prospective cohort study revealed positive associations between exposure to the widely used glutamate food additives, especially MSG (E621) and CVD, CVA, and CHD risks. • If confirmed, our findings regarding MSG could lead to a re-evaluation of the safety of these food additives by European and international public health agencies to improve consumer protection.