Tumor necrosis factor (TNF) is a macrophage-derived mediator responsible for many of the pathophysiologic manifestations of endotoxic shock. We now demonstrate that amrinone, a noncatechol inotrope, strongly inhibits lipopolysaccharide (LPS)-induced TNF production at concentrations readily achieved in vivo. This inhibition is apparent in murine macrophages, in macrophage cell lines, in vivo, and in cell lines containing a reporter gene construct that substitutes the chloramphenicol acetyl transferase (CAT) coding sequence for the TNF coding sequence and introns. Inhibition by amrinone (like inhibition by pentoxifylline) is manifested at the level of mRNA accumulation, in contrast to inhibition caused by dexamethasone. Combined application of dexamethasone and amrinone caused additive inhibition of TNF biosynthesis in vitro. Furthermore, treatment of mice with amrinone immediately prior to endotoxin challenge led to significantly improved survival. These findings suggest that amrinone possesses antiinflammatory as well as inotropic properties that may make it an appropriate agent for use in septic shock or other serious bacterial infections. Abrupt removal of amrinone or pentoxifylline from the culture medium prior to LPS stimulation, however, caused significantly augmented TNF production. Therefore, amrinone and other phosphodiesterase inhibitors may also enhance sensitivity to LPS during a period of time following discontinuation of therapy.