Two groups of eight male Normalized/National Institutes of Health (N/Nih) rats were used in a food-motivated, 2-lever drug discrimination task with one group being trained to discriminate between 10 mg/kg cocaine vs. 1 g/kg ethanol, whereas the second group was trained to discriminate the metabolic product of these two agents, i.e., cocaethylene (10 mg/kg) vs. its saline vehicle. All drugs were administered intraperitoneally and training/testing was conducted 15 min post-injection. Once both groups of animals attained criterion performance, they were each tested in sessions, interspersed with maintenance sessions, with numerous doses of both cocaine and cocaethylene; this resulted in a typical dose-response relationship in each group but indicated that the cocaine-ethanol trained animals were more sensitive to the lower doses of cocaine (as indicated by a decreased ED50 value, i.e., 1.74 mg/kg) when compared to previously trained cocaine-saline animals (ED50 4.22 mg/kg) and, that in both groups, cocaine was significantly more potent than was cocaethylene. Although numerous laboratories have trained drug vs. drug in the drug discrimination paradigm, this is the first study to train animals to discriminate between two drugs which, although having different discriminative properties, form a third psychoactive compound when co-administered. The sensitivity of drug-drug testing vs. drug-saline testing is discussed, as well as the use of these two agents in human abuse.