Prolactin (PRL) plasma levels rise several fold in response to electroconvulsive therapy (ECT). There is evidence that the magnitude of ECT-induced PRL release varies as a function of electrode placement with bilateral (BL) ECT, producing a larger PRL increase than does unilateral (UL) ECT. Although there is some evidence that the amount of PRL released by ECT may also vary as a function of stimulus intensity, the effect of stimulus intensity on the amount of PRL released by UL ECT has not been studied. This is an important question because it is with UL electrode placement that large differences in clinical efficacy as a function of stimulus intensity have been documented. We studied patients undergoing a course of UL ECT as the clinically indicated treatment for their illness. Subjects received low-dose (threshold) and high-dose (three times the threshold) ECT on two consecutive treatments. The order of low- and high-dose treatments was counterbalanced. Blood samples were drawn at 15-minute intervals before and for 1 hour after the administration of ECT and assayed for PRL and cortisol levels. Our results clearly indicate that the PRL and cortisol response to UL ECT-induced PRL release varies as a function of stimulus intensity. In fact, the amount of PRL released by high-dose UL ECT was nearly three times greater than that released by threshold stimulation. These results are consistent with the hypothesis advocating that the therapeutic advantage of high-intensity over low-intensity UL ECT is the result of greater seizure generalization and spread to subcortical regions and suggest that ECT-induced PRL release has the potential to distinguish a seizure induced by a therapeutic stimulus from a seizure induced by a stimulus known to have little therapeutic effect.