Cocaethylene is a pharmacologically active cocaine metabolite that is produced in the liver by the transesterification of cocaine only in the presence of ethanol. The acute cardiovascular effects of cocaethylene are not known. We compared the acute cardiovascular effects of cocaethylene with cocaine and with cocaine plus ethanol in 18 dogs. We administered cocaethylene 7.5 mg/kg to 6 dogs, cocaine 7.5 mg/kg to 6 dogs, and cocaine 7.5 mg/kg plus ethanol 1 gm/kg to 6 dogs. The dose of each drug was chosen to produce in dogs the concentrations of cocaethylene or cocaine that have been measured in patients who have experienced cardiotoxic reactions to cocaine or cocaine plus ethanol. Arterial, left ventricular (LV), pulmonary artery wedge pressures (PAWP), the maximum rate of LV pressure rise [(dP/dt)max] and fall [(dP/dt)min], and heart rate (HR) were continuously measured. Stroke volume was determined 3 times during the first hour after drug administration then hourly for four hours. The concentrations of cocaethylene and cocaine peaked in the serum at 3717 +/- 651 ng/ml and 4140 +/- 459 ng/ml, respectively, two minutes after each bolus. The median half-life of cocaethylene was 144.3 minutes whereas the median half-life of cocaine was 96.7 minutes (p < 0.01). Cocaethylene maximally decreased (dP/dt)max by 44%, (dP/dt)min by 29%, and stroke volume by 28% (all p < 0.01) and increased the PAWP by 50% (p < 0.02) and the HR by 13% (p = NS) during the first hour. Cocaine maximally decreased (dP/dt)max by 40%, (dP/dt)min by 31%, and the stroke volume by 26% and increased the PAWP by 100% and the HR by 46% (all p < 0.01) during the first hour. Ethanol plus cocaine maximally decreased (dP/dt)max by 68%, (dP/dt)min by 78% and the stroke volume by 49% and increased the PAWP by 118% and the HR by 74% (all p < 0.01) during the first hour. In this last group, (dP/dt)max and stroke volume remained depressed by approximately 20% (p < 0.01) for five hours. We conclude that cocaethylene is as toxic as cocaine to the myocardium but is less toxic than ethanol plus cocaine.