Background: High feed osmolality (or osmolarity) is often suggested to be linked with adverse gastrointestinal events in preterm infants. Aim: To systematically review the literature on milk feed osmolality and adverse gastrointestinal events in newborn and low birthweight infants and animals. Methods: MEDLINE, Embase, CAB Abstracts, Current Contents, BIOSIS Previews and SciSearch were searched from inception to May 2018 to identify potentially relevant studies. Inclusion criteria: randomised controlled or observational studies of newborn and low birthweight infants or animals investigating the effects of milk-based feeds with different osmolalities. Only full-text, English-language papers were included. Results: Ten human and six animal studies met the inclusion criteria. Of human studies, seven reported no differences in adverse events with varying feed osmolalities; one reported delayed gastric emptying with feed osmolarity of 539 mOsm/L compared with lower levels; one reported higher necrotising enterocolitis (NEC) incidence with feed osmolarity of 650 mOsm/L compared with 359 mOsm/L; one found higher NEC incidence with the lowest feed osmolality (326 mOsm/kg compared with 385 mOsm/kg). Of animal studies, two reported delayed gastric emptying with feed osmolarity >624 mOsm/L, one reported decreased survival due to dehydration with dietary osmolarities ≥765 mOsmol/L and none reported increased NEC incidence with differing feed osmolalities. No clear mechanisms were found, and diet composition differences limited the interpretations regarding the independent impact of osmolality. Conclusions: There is no consistent evidence that differences in feed osmolality in the range 300-500 mOsm/kg are associated with adverse gastrointestinal symptoms in neonates.