A number of studies indicate that stress can result in suppression of the immune system in animals and man. Most of the studies have focused on alterations of lymphocyte function while only a few have investigated alterations of macrophage function or macrophage cytokine production. Macrophages play an essential role in homeostasis of the immune response. Indeed, the earliest events of the immune response occur in cells of the monocytic lineage, and their secretion of various cytokines may have both immunological and nonimmunological effects. The present studies were undertaken to determine whether alterations in macrophage physiology occur in mice subjected to a stress stimulus. Our studies in mice exposed to cold water stress for 4 days indicated reduced numbers of thymocytes and splenocytes, decreased T-cell blastogenesis, and reduced NK activity. Examination of elicited peritoneal macrophages from stressed mice revealed increased prostaglandin E2 (PGE2) secretion and decreased immune region associated antigen (Ia) expression in response to interferon-gamma. Despite elevated PGE2 levels, indomethacin was generally unable to restore depressed immune function. Of special interest was the finding that cell-associated and secreted interleukin 1 were significantly higher from unstimulated elicited macrophages from stressed mice. These results suggest that early in the response to stress, functions of a variety of cells within the immune system, especially macrophages, are altered and that dysregulated macrophage function may well contribute to the generalized suppression of the immune response in cold water stressed mice.