The effects of physiological concentrations of beta-endorphin on the proliferative response to concanavalin A of human peripheral blood mononuclear cells from a large series of healthy donors are reported. These effects are also compared with those obtained employing beta-endorphin and phytohemagglutinin under the same experimental conditions. The donors (32), aged between 20 and 48 years, chosen among military personnel of the Italian Air Force, underwent clinical and laboratory investigations to exclude any detectable disturbance in their psychophysical fitness. Our results show that beta-endorphin is not mitogenic per se and is unable to modify the response of mononuclear cells to phytohemagglutinin irrespective of the concentration of opioid or mitogen used. beta-Endorphin is also unable to alter the PBMC response to low concentrations of concanavalin A, but significantly increases such a response when higher concentrations of concanavalin A and concentrations of beta-endorphin similar to those found in human plasma under physiological conditions are used. The effect is not reverted by naloxone, the specific opiate antagonist. When the activity of beta-endorphin on the mononuclear cell response to concanavalin A is examined at the single donor level, it is noted that some of the donors fail to show the opioid-dependent increase. The baseline levels of the response to concanavalin A of such subjects, compared to those of the donors whose response is augmented by the opioid, are significantly higher, thus demonstrating that beta-endorphin can selectively modulate concanavalin A-induced mitogenesis with a behavior depending on the individual characteristics of the donor's response. The process involves non-opioid cell receptors.