While the cardiovascular effects of endotoxin include myocardial depression, presumably due to circulating myocardial depressant substances, endotoxin itself is supposed to have no direct effect on the heart. In these experiments, we compared the direct effects of endotoxin on the contractile response of feline papillary muscle to calcium with that seen after administration to the intact animal. The contractile state of the muscle was assessed from developed tension as extracellular calcium concentrations were varied from .5 to 8.0 mM. When endotoxin was administered to the intact animal as well as given to the muscle directly in the bathing solution, endotoxin- exposed muscles showed smaller increases in contractile tension with increasing calcium concentrations than control muscles after 70-85 min. NaOH-inactivated endotoxin produced results similar to the control experiments. Previous experimenters have reported myocardial depression only after endotoxin had circulated in the intact animal for 1-2h; these experiments show a direct depressant effect of endotoxin on cardiac muscle without the release of a substance elsewhere in the body.