Newborn endotoxic shock syndrome is associated with high morbidity and mortality, yet presents with different clinical manifestations than in older patients. To determine the influence of age on hemodynamic and metabolic responses to endotoxin, we developed a chronically instrumented endotoxic shock model using eight 1-3-day-old and seven 2-3-week-old piglets. Three days after surgery, 10 mg/kg of endotoxin was infused intravenously over 10 min in the younger group, and 5-10 mg/kg was given to the older animals. Two older piglets died immediately after infusion of 5 mg/kg of endotoxin, and five of the seven died within 4 hr, while all eight younger animals lived longer than 4 hr. Pulmonary artery pressure increased significantly after endotoxin in both groups, and there were no differences between groups. Systemic artery pressure and cardiac index fell by 44 ± 10% and 70 ± 15%, respectively, 5 min after endotoxin infusion in the older group, while these values did not change significantly in the younger group. Endotoxin infusion also caused greater elevation in pulmonary vascular resistance index in the older animals. In the later phase, which began 30 min after endotoxin, both groups displayed systemic hypotension and pulmonary hypertension, and the groups did not differ from one another in this regard. With progression of endotoxic shock, more severe metabolic acidosis developed in the older animals than in the younger animals. Plasma thromboxane B2 levels in the older group were about double those in younger piglets. Plasma 6-keto- PGF(1α) and TNF(α) levels in both groups were similar and were significantly increased in the later phase. These results demonstrate age- related differences in response to endotoxin in unanesthetized infant piglets. The reasons underlying the different age-related responses to endotoxin may be attributed to anatomic and physiologic immaturity in the developing newborn; these distinctions may be important in pathogenesis of human disease.