In this secondary analysis of the Mega Donna Mega (MDM) randomized clinical trial including 177 extremely preterm infants, a faster rise in blood levels of the metabolic stress-induced protein fibroblast growth factor 21 (FGF-21) in the first postnatal days distinguished extremely preterm infants who later developed severe ROP. Here, FGF21 is linked to retinopathy of prematurity.