Three clinical trials enrolling 418 infants (less than or equal to 1500 g birth weight) and an ultrastructural data base of 71 pairs of whole eye donations have elucidated the efficacy of vitamin E in suppressing the development of severe retrolental fibroplasia (ROP). Only continuous vitamin E supplementation to adult physiologic levels from the first hours of life suppresses the development of severe ROP. Supplementation does not increase the incidence of necrotizing enterocolitis, sepsis, intraventricular hemorrhage, or mortality. Only multivariate analysis, which considers all risk factors simultaneously, is appropriate when appraising the efficacy of supplementation since all the clinical risk factors uniquely impinge on the oxygen dynamics of the developing retina. Mesenchymal spindle cells are the cellular mediators of the induction of ROP by oxygen in which increased oxygen tension triggers extensive gap junction formation between adjacent spindle cells. This cellular event, which occurs as early as four days of life, halts the normal vasoformative process and triggers neovascularization, which becomes clinically evident some 8 to 12 weeks later.