To test whether endogenous opioid peptides are necessary for the rewarding effects of ethanol, we examined operant oral self-administration of ethanol in mice congenic to the C57BL/6J strain but lacking expression of beta-endorphin, enkephalin or both peptides. The influences of prandial state, schedule interval and type, and ethanol concentration were all examined. Food-restricted subjects were tested in postprandial and preprandial states and subsequently at normal body weight when feeding ad libitum (ad lib). Operant studies were conducted using fixed ratio (FR) intervals of 2 and 8 as well as a progressive ratio (PR) interval of 2. The main significant effect relevant to our hypothesis was increased responding by female mice lacking beta-endorphin under ad lib feeding conditions and only for lower ethanol concentrations (3% and 6%). Importantly, all subjects including those lacking both beta-endorphin and enkephalins learned to self-administer ethanol similarly to wild-type mice and maintained responding for ethanol under a variety of procedural variables. Consequently, the two opioid peptides believed to be the endogenous ligands for the micro-opioid receptor (MOR) were not necessary to shape or perpetuate ethanol-reinforced operant responding. These results suggest that the rewarding effects of ethanol do not require beta-endorphin or enkephalin signaling.