Background The opioid peptide β-Endorphin (β-E) is synthesized and released in response to stressful stimuli as well as acute alcohol administration. The release of β-E following exposure to an inescapable aversive situation may mediate behaviors that contribute to allostasis of the stress response. The present study examines the effects of β-E on immobility in assays involving inescapable stress, both under basal conditions as well as after acute administration of EtOH. Methods Female and male transgenic mice with varying capacities to translate β-E were subject to either the forced swim (FST, Experiment 1) or tail suspension test (TST, Experiment 2). In Experiment 3, mice were divided into three groups based on hormonal status (male, female-estrous and female-nonestrous) and injected with either 1 g/kg EtOH or equivolume saline 14 min prior to behavioral assessment on the TST. Results Experiments 1 and 2 demonstrated a direct relationship between β-E levels and immobility. There were also sex differences in behavior in these tests, with males displaying more immobility than females. A main effect of genotype in Experiment 3 replicated findings in Exp 1 & 2. There was also an effect of EtOH (increasing immobility) and a significant interaction reflecting a particularly robust effect of the drug in mice with low β-E. In addition, there were interactions between β-E, EtOH effects and hormonal status. Conclusions These findings support the contention that β-E moderates behavioral responses to stressful stimuli and suggest a role for this peptide in coping behavior. Furthermore, the effects of EtOH on the response to stress may be mediated by β-E. Sex differences in this influence may contribute to sex differences in disease susceptibility and expression.