As part of the Pre-B Project, a systematic review was conducted to evaluate associations between exclusive maternal milk (≥75%) intake and exclusive formula intake and growth and health outcomes in very-low-birthweight (VLBW) preterm infants. The protocols from the Academy of Nutrition and Dietetics' Evidence Analysis Center and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist were followed. Thirteen observational studies were included; 11 studies reported data that could be synthesized in a pooled analysis. The evidence is very uncertain (very low quality) about the effect of exclusive maternal milk on all outcomes due to observational study designs and risk of selection, performance, detection, and reporting bias in most of the included studies. Very-low-quality evidence suggested that providing VLBW preterm infants with exclusive maternal milk was not associated with mortality, risk of necrotizing enterocolitis, sepsis, or developing bronchopulmonary dysplasia, as compared with exclusive preterm formula, but exclusive maternal milk was associated with a lower risk of retinopathy of prematurity (very low certainty). Results may change when additional studies are conducted. There was no difference in weight, length, and head circumference gain between infants fed fortified exclusive maternal milk and infants receiving exclusive preterm formula; however, weight and length gain were lower in infants fed non-fortified exclusive maternal milk. Given the observational nature of human milk research, cause-and-effect evidence was lacking for VLBW preterm infants.