It has been well documented that the administration of hypertonic substances to the newborn may result in a variety of adverse effects, including hepatic, intestinal, and/or neuronal injury. Furthermore, neonates are exposed to a large number of drugs and other substances while in the intensive care nursery setting. As few data are available that document the actual osmolality of many of the substances employed in caring for the sick neonate, the present study measured the osmolality of 64 medications as well as 23 formulas or nutritional supplements used in the intensive care nursery. Osmolality was determined by both vapor pressure and freezing point depression. Results indicate that a large number of medications normally administered by the enteral route possess a markedly elevated osmolality in excess of 2,000 mosm/kg H2O. Although parenterally administered medications normally have a much lower osmolality, several possess significantly elevated levels. It is recommended that measures be taken to minimize the osmolality of substances administered to the critically ill newborn whenever possible.