Opioid peptides are found to be released from cells of the immune system during inflammation and stress, and are associated with altered immune responses. Moreover, concentrations of opioid peptides are increased in peripheral blood and at the sites of inflammatory reactions. Inflammatory responses to infection in vivo are initiated by directed migration of phagocytes, neutrophils and macrophages in peripheral tissue, and microglia in the brain, into the sites of infection. The migration follows in phagocytosis of the invading microorganisms and killing by generation of reactive oxygen species such as superoxide anion. Endomorphins 1 and 2 are recently isolated endogenous opioid peptides, and potent and selective high affinity μ-opioid receptor agonists. First, we have examined effects of endomorphins 1 and 2 on chemotaxis, phagocytosis and superoxide anion production in phagocytes. Endomorphins 1 and 2 potentiated chemotaxis in neutrophils, whereas they inhibited chemotaxis in macrophages and microglia. In addition, both endomorphins blocked phagocytosis of Escherichia coli by microglia, without affecting that by neutrophils and macrophages. Moreover, endomorphins 1 and 2 blocked the production of superoxide anion by neutrophils and macrophages, whereas they potentiated that by microglia. The next attempt was to examine effects of endomorphins 1 and 2 on particular functions of each phagocyte. Endomorphins 1 and 2 inhibited neutrophil adhesion, whereas they potentiated macrophage adhesion. Moreover, both endomorphins significantly delayed constitutive neutrophil apoptosis via phosphoinositide 3-kinase pathway. In contrast, endomorphins 1 and 2 inhibited tumor necrosis factor-α, interleukin (IL)-10 and IL-12 productions, but potentiated IL-1β production by macrophages. Therefore, endomorphins may differentially modulate the immune functions in neutrophils, macrophages and microglia.