• Electroconvulsive therapy is accompanied by an activation of the hypothalamic-pituitary-adrenal axis, resulting in a release of β-endorphin from the anterior pituitary corticotrophs of humans. As a group, patients in our study demonstrated similar plasma β-endorphin immunoreactivity response to their initial and final treatments. However, approximately half of the patients demonstrated greater β-endorphin immunoreactivity release with their first seizure compared with their last seizure, and half of the patients demonstrated the opposite pattern. This difference was not explained by age, sex, unilateral vs bilateral treatments, sine wave vs brief pulse, or psychotropic or anticholinergic medication. Patients with constant seizure duration during the first and final treatments demonstrated a greater release of β-endorphin immunoreactivity with the final treatment compared with the first treatment. Individuals with decreasing seizure duration during the course of the electroconvulsive therapy demonstrated a decreased β-endorphin immunoreactivity response during their final treatment.