Interleukin (IL)-2 is not only an immunoregulatory factor, but also an analgesic molecule. There are distinct domains of immune and analgesic functions in the IL-2 molecule. The analgesic domain is located around the 45th Tyr residue of human IL-2 in tertiary structure. Antiopioid (β-endorphin, Leu-enkephalin, Met-enkephalin and dynorphin A1–13) sera partially neutralized the analgesic activity of IL-2. Monoclonal antibody against the IL-2 receptor α subunit (Tac) could not block the analgesic activity of IL-2. There existed cross-reactivity between IL-2 and antiopioid sera by indirect ELISA. These studies show strong structural and biological similarities between IL-2 and opioid peptides. The tertiary structure around the 45th residue of IL-2 composes the analgesic domain that is similar to that of endogenous opioids. These results are consistent with the hypothesis that multiple domains of cytokines serve as the structural bases for the immunoregulatory and neuroregulatory effects of cytokines.