Background: The use of human milk for premature infants is increasing but the contributions of standard fortified human milk (FHM) to host defense are unclear. Subjects: Premature infants were evaluated in hospital: Group I (n=38) fed FHM only, Group II (n=82) fed FHM and preterm formula (PF), Group III (n=43) fed PF only. Interventions: Measures of infant morbidity. Results: The mean (±SD) birth weight (1.0±0.2 kg), gestational age(28±1 wk), gender, ethnicity, use of central venous catheters, amount of milk consumed, and receipt of antenatal steroids were similar among groups. The groups had similar incidence of bronchopulmonary dysplasia and duration of parenteral nutrition. Necrotizing enterocolitis differed significantly among groups (p < 0.05): Group I=3%, Group II=18%, Group III=9%. Group I had significantly fewer positive blood cultures, episodes of sepsis, and less antibiotic usage than Groups II and III, p < 0.05. The use of the mother-infant skin-to-skin protocol was significantly greater in Group I than II & III p < 0.001. Group I had a shorter hospital stay (69±25 d) than Group II (85±37 d) or III (86±45 d),p=0.01. Conclusion: These data suggest that the exclusive use of FHM contributes to healthier premature infants who have shorter hospital stays, potentially reducing the cost of medical care.