The effect of morphine on the degradation of the host defense barrier in rats and mice was studied. Mice received either 3 or 11 doses of morphine. Mice receiving 11 doses of morphine showed gram-negative bacteremia and bacterial growth in samples of peritoneal fluid (PF), liver, spleen, kidneys, heart, and lungs; PF and tissue samples from only 1 control mouse showed bacterial growth, and no control mice had bacteremia. Mice receiving 11 doses also had suppressed bone marrow macrophage colony formation. Monocytes and peritoneal macrophages harvested from morphine-treated mice showed greater injury than did those from control mice. Pretreatment of mice with naloxone inhibited morphine-induced macrophage injury and degradation of the host defense barrier. In in vitro studies, morphine attenuated the killing of bacteria phagocytosed by macrophages and also facilitated their escape. This study indicates that morphine-induced monocyte and macrophage injury may be linked to degradation of the host defense barrier.