These studies investigated the effect of met-enkephalin, glycyl-glutamine, and naltrexone on NK cell activity in vivo and in vitro. It was found that both met-enkephalin (which shares the amino-terminal end of βendorphin) and glycyl-glutamine (which reflects the carboxyl-terminal end of βendorphin) can enhance the NK cell activity of mice prestimulated with a low dose (1 μg/mouse) of poly I:C. Naltrexone had no effect. In vivo prestimulation of the mice with 1 μg poly I:C was necessary as mice which were not pretreated with poly I:C did not show enhanced NK cell activity when treated with either met-enkephalin or glycyl-glutamine. In vitro studies however indicate that the drugs when cultured together with the NK cells from mice preactivated with poly I: C did not have a direct stimulatory effect on the NK cells. These studies imply that while βendorphin released from the pituitary could be involved in enhancement of activated NK cells in vivo other indirect peripheral pathways might be involved. The results suggest βendorphin probably reacts with other accessory type cells which in turn release the mediators which are required for the stimulation of NK cells in vivo. © 1991 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.