Natural Killer (NK) activity of lymphocytes from acquired immunodeficiency syndrome (AIDS) patients is frequently below normal and declines as disease progresses. We studied the potential of leucine enkephalin (leu-enkephalin) to restore this immune parameter by incubating nylon wool nonadherent mononuclear cells from 14 patients in the presence or absence of leu-enkephalin, and measuring NK cytolysis in a standard 51Cr release assay. The NK activity of human immunodeficiency virus antibody positive (HIV+) individuals with some remaining NK lytic ability was significantly augmented by leu-enkephalin concentrations of 10(-10) and 10(-8) M (n = 7). HIV+ patients with no measurable basal level of NK activity (n = 3) were not responsive to stimulation with leu-enkephalin. Human immunodeficiency virus antibody negative (HIV-) individuals (n = 4) responded in a pattern similar to normals. In addition, naloxone, an antagonist of alkaloid and peptide opiates including leu-enkephalin, displayed the properties of an antagonist/agonist, reflecting the immunoregulatory capacities of the endogenous opiate system.