The involvement of endorphins in the ovine cardiopulmonary response to endotoxin was evaluated by measuring blood levels of opiate receptor binding substances and administering the opiate receptor blocking agent naloxone prior to and after the administration of lipopolysaccharide. The animals were prepared for chronic study by placement of cardiovascular catheters and cannulation of the lung lymphatic at least 1 wk prior to study. The sheep were given endotoxin (0.75 μg/kg) and studied for 6 h. This was accomplished twice in the same animal. Naloxone (2 mg/kg bolus + 2 mg.kg-1.h-1) was given with one of the two doses of the lipopolysaccharide. The response to endotoxin could be divided into two phases. In phase 1, there was an increase in protein-poor lung lymph and a marked increase in pulmonary artery pressure. In phase 2, the pulmonary lymph flow was elevated but the lymph protein level was higher than in phase 1. The pulmonary artery pressure, however, was near normal. During both phases leukocytes and cardiac output were reduced and the hematocrit was elevated. There was an increase in opiatelike materials in the plasma of these animals, and the response to endotoxin was partially blocked by naloxone. This suggested that endorphin-like materials were involved in the response to endotoxin.