OBJECTIVE: We hypothesized that fetal lipopolysaccharide exposures to the chorioamnion, lung, or gut would induce distinct systemic inflammatory responses. STUDY DESIGN: Groups of 5-7 time-mated ewes were used to surgically isolate the fetal respiratory and the gastrointestinal systems from the amniotic compartment. Outcomes were assessed at 124 days gestational age, 2 days and 7 days after lipopolysaccharide (10 mg, Escherichia coli 055:B5) or saline solution infusions into the fetal airways or amniotic fluid. RESULTS: Lipopolysaccharide induced systemic inflammatory changes in all groups in the blood, lung, liver, and thymic lymphocytes. Changes in lymphocytes in the posterior mediastinal lymph node draining lung and gut, occurred only after direct contact of lipopolysaccharide with the fetal lung or gut. CONCLUSION: Fetal systemic inflammatory responses occurred after chorioamnion, lung, or gut exposures to lipopolysaccharide. The organ responses differed based on route of the fetal exposure.