Both physiologic stress and chronic heart disease are associated with increased systemic levels of chromogranin A (CGA) and NT-proBNP. Marathon running causes physiological stress and imposes a significant cardiac burden. Polyphenol-rich Mediterranean and Asian diets have been demonstrated to exert beneficial effects on the cardiovascular system. In this study we investigated whether pretreatment with a polyphenol beverage could attenuate the physiological and cardiac stress associated with a marathon. In the BeMaGIC trial, 277 athletes were randomized into 2 groups in a double-blinded fashion, receiving 1-1.5 L/day of the same beverages either with (study beverage) or without (placebo) polyphenol enrichment (approximately 400 mg of gallic acid equivalents per day of a complex mixture of polyphenols). Blood samples were taken 3 weeks and 1 day before, and immediately, 24 h, and 72 h after running a marathon. In our current substudy, CGA and NT-proBNP levels were analyzed by ELISA in the fastest 18 and the slowest 22 runners. CGA and NT-proBNP levels increased significantly immediately after the marathon and returned to baseline at 72 h after the marathon. Neither CGA nor NT-proBNP differed significantly between athletes receiving study beverage versus placebo. Separating our cohort into fast and slow runners did not reveal any significant difference regarding CGA or NT-proBNP levels between groups. Our study provides no evidence that polyphenol supplementation attenuates marathon running-induced physiological stress and cardiac burden in fast or slow runners.