OBJECTIVES: To determine the incidence of pulmonary fat embolism after the intraosseous (IO) infusion of normal saline and drugs and to determine whether pulmonary capillary blood is a predictor of lung fat embolism. DESIGN: A randomized, prospective, animal study. SETTING: Animal research laboratory of a university hospital. SUBJECTS: Twenty-eight mixed breed piglets (average weight 30.9 kg). Interventions and Methods: Animals were anesthetized, intubated, mechanically ventilated, and instrumented. IO needles were placed in the tibial bone. Animals were assigned to one of four groups: Group 1 received fluid (20 mL/kg) under 300 mm Hg pressure (n = 6); group 2 received fluid (20 mL/kg) at free flow under gravity (n = 6); group 3 received 100 mL of fluid over 20 mins (n = 8); and group 4 received 100 mL of fluid over 7 mins (n = 8). MEASUREMENTS AND MAIN RESULTS: Buffy coat samples were obtained from pulmonary arterial catheter in the occluded position at baseline, after IO needle placement, and at the end of infusion. Lung specimens (both upper and lower lobes) were obtained at the end of the infusion. Specimens were stained with oil red O and graded for fat emboli by a pathologist blinded to experimental conditions. Fat emboli (one to three emboli per high power field) were found in about 30% of the lung specimens. The difference in number of fat emboli between groups was not statistically significant. Buffy coat stains yielded fat emboli, which were distributed sporadically in all groups. CONCLUSION: Fat embolism is common; however, the method of IO fluid administration does not influence the number of emboli. Our study therefore implies that the risk of fat embolization is of concern, but its clinical relevance is unclear. Until the clinical significance of pulmonary fat emboli and the prevalence of fat emboli syndrome are delineated more precisely, the IO route is an effective but not necessarily safe route for delivery of fluids and drugs.