BACKGROUND AND AIMS:Polyphenol-rich diets have been associated with reduced risk of cardiovascular disease (CVD). However, few prospective epidemiological studies have examined the relationship between classes of ingested polyphenols and risk of CVD. Our aim was to evaluate the association between polyphenol intake and risk of major cardiovascular events in a prospective Spanish cohort. METHODS AND RESULTS:We included 17,065 university graduates (60.7% women, mean age: 37.2 years, age range: 20-89) followed-up for a mean of 10.1 years. Polyphenol intake was assessed at baseline using a validated semi-quantitative 136-item food frequency questionnaire and matching food consumption data with the Phenol-Explorer database. Cox proportional hazards models were used to estimate the adjusted hazard ratios (HR) and 95% confidence intervals (95% CI) for incident cardiovascular events (myocardial infarction, stroke or cardiovascular death). Cherries, chocolate, coffee, apples, and olives were the major sources of variability in polyphenol intake. Participants with higher flavonoids intake (fifth quintile) had a 47% lower incidence of cardiovascular events compared to those in the lowest quintile (HR: 0.53, 95% CI: 0.29-0.98; P for trend = 0.09) after adjusting for potential confounders. The results were non-significant for other polyphenol types. CONCLUSION:The intake of flavonoids showed an inverse association with risk of cardiovascular events in a prospective cohort of Spanish middle-aged adult university graduates. REGISTRATION NUMBER FOR CLINICAL TRIALS:NCT02669602 in Clinical Trials.