Opioids represent a major source of relief for acute and chronic, moderate to severe nonmalignant pain. However, opioid abuse may cause immunosuppression leading to infections and cancer development. Recently we reported results on novel non-peptidic delta- and mu-selective opioids that induced immunopotentiation in vitro and ex vivo. In the present study, we investigated the effects of the delta agonist SNC 80, and mu agonists, naltrindole and naltrexone derivatives for their capacity to alter lymphoproliferation in vitro. They were observed to stimulate lymphoproliferation at concentrations ranging from 10(-10) to 10(-5) M. SNC 80 significantly (p<0.05) stimulated (43-311%) proliferation of resident and concanavalin A (Con A)-treated lymphocytes; the naltrindole derivatives 9332 and 9333 caused significant (p<0.05) 26-47% and 13-43%, respectively, stimulation of Con A-treated lymphoproliferation; whereas the naltrexone derivatives 9334 and 9336 significantly (p<0.05) stimulated 9-40% and 15-69%, respectively, proliferation of resident and Con A-treated lymphocytes. These novel opioid ligands could serve as immunotherapeutic agents by increasing the pool of lymphocytes with potential use in the treatment of infectious diseases including AIDS. This study provides evidence of the relationship structure/function of opioids on lymphoproliferation, and supports further evaluation of opioids with immunomodulatory potential in preclinical and clinical studies.