This study was carried out to investigate the relative time courses of the presence of a reticuloendothelial (RE) depressing substance and reticuloendothelial system (RES) phagocytic function following thermal injury in animals: additionally, RE depressing activity was determined in burned patients. Following thermal injury in dogs, RE depressing activity was first detected 2 hr after injury and persisted for 12 hr. RE depressing activity was present in the circulation of burned rats at 3 and 24 hr but not 48 hr after injury. RES phagocytic function was also depressed at 3 and 24 hr but not at 48 hr after thermal injury in rats, showing that there was a close association between the presence of RE depressing activity and RES depression. Injection of RE depressing substance into normal animals depressed the RES for less than 60 min. Five of six burned patients studied within 5 days after injury had detectable RE depressing activity in their circulation. These findings further support the concept that a RE depressing substance contributes to the depression of RES phagocytic function and impairment of host defense following thermal injury.