Gram-negative sepsis causes a depression of the myocardium such that ventricular function curves generated on isolated perfused hearts removed from septic rats are displaced downward and to the right of control. Alcohol consumption can also cause a depression of the myocardium, especially if the period of alcohol feeding is prolonged. However, even before overt changes in the myocardium can be measured as a result of alcohol consumption, chronic alcoholism can result in a potentiation of sepsis-induced cardiac depression (Am. J. Physiol. 250:H1857-H1863, 1991). The purpose of the present study was to determine if 1 week of withdrawal of alcohol from the diet after 8 weeks of alcohol consumption would reverse the potentiation by alcohol of sepsis-induced cardiac depression. Animals were fed an ethanol-containing diet in which ethanol contributed 36% of the total calories. Rats were fed this diet or a control liquid diet for 8 weeks, and then some animals were taken off the alcohol diet and placed on the control diet for 1 week. Sepsis was induced in control-fed, alcohol-fed or withdrawal animals by the administration of Escherichia coli into the dorsal subcutaneous space. Nonseptic animals received sterile saline in this space. The following day animals were anesthetized, and the hearts were removed and studied as isolated working hearts. Hearts removed from septic and alcohol septic animals showed severe depression of cardiac contractile performance. Hearts from the withdrawal group, however, were less compromised by sepsis and showed only a few signs of cardiac dysfunction. Withdrawal from alcohol for 1 week thus resulted in protection of the heart from sepsis-induced cardiac depression.