The role of lipopolysaccharide (LPS) as an activator of human monocyte interleukin-1 (IL-1) synthesis and secretion has been examined in this study. The results demonstrate that when blood monocytes are prepared under low endotoxin conditions, they do not spontaneously secrete IL-1 activity. When cells are exposed to LPS extracted from different bacterial species, there is variation seen in the potency, with LPS from Salmonella species being the most potent in inducing IL-1 activity from human monocytes. This material is tenfold more potent than LPS obtained from three different strains of Escherichia coli and 10,000-fold more potent than material obtained from two other bacterial species. Detoxified endotoxins are inefficient activators for IL-1 secretion. When monocytes are exposed to LPS, there is a rapid rise in the level of IL-1 activity detected. Activity can be detected in cell lysates after 1 hr with appreciable accumulation seen over the first 6 hr of culture. This is accompanied by IL-1 release into the surrounding medium after 2 hr of culture with subsequent accumulation. Monocyte synthesis of IL-1 activity appears to be sensitive to fg/ml levels of Salmonella minnesota LPS, while appreciable secretion of this activity by monocytes requires pg/ml levels.