Human milk (donor milk (DM) and/or maternal milk (MM)) feedings protect against late onset sepsis (LOS), necrotizing enterocolitis (NEC) and death. However, DM lacks many anti-infective components of MM. Therefore, we studied exclusive MM feedings to evaluate the full effect of human milk on infectious and other outcomes in premature infants. All infants born before 33 weeks postmenstrual age (PMA) who received exclusive (>95%) MM or exclusive preterm formula (PF) were included in this prospective investigation. Sixty-three infants (53%) received MM and 55 infants (47%) received PF. Both groups had similar baseline characteristics. Infants in the MM group achieved full enteral nutrition sooner (14±8 vs 19±15 days, P<0.03) and required a shorter duration of central venous lines (14±10 vs 22±21, P<0.005). Fewer infants in the MM group developed LOS (9 vs 19, P<0.05) and pneumonia (8 vs 16, P<0.05) than PF infants. Only one MM and five PF infants developed NEC (Bell stage ⩾II). Logistic regression analysis using PMA and prolonged rupture of membranes as covariates demonstrated an increased rate of NEC (odds ratio=8.85, CI=1.01 to 25.17, P=0.048) in PF infants. Periventricular leukomalacia (PVL) was more common in PF (4 vs 0, P=0.04) than in MM infants. Feedings of MM advanced more rapidly and were associated with fewer infections than PF. A possible protective effect of MM against PVL, not previously described, may be related to its immune and anti-inflammatory components.