We have shown previously that whereas acute exposure of cultured murine peritoneal macrophages inhibits phagocytosis, chronic exposure results in a putative tolerant/dependent state. We now report similar observations using human cultured monocyte-derived macrophages (hMDM) from a control population and from methadone patients. With hMDM, acute exposure to morphine and methadone inhibited phagocytosis in a dose-dependent manner. In contrast, chronic exposure resulted in eventual normalization of phagocytosis, indicating that a putative tolerant state to the opiates had developed. When opiates were withdrawn from chronically-exposed, tolerized hMDM, phagocytosis was once again depressed. The duration of withdrawal-induced depression lasted several hours, which is much longer than evidenced previously with murine macrophages. These data identify well with various in vivo studies on immune effects of opiate withdrawal; and, in so-doing, supplement ongoing speculation that opiate withdrawal is likely to have serious impact on host defenses of street heroin addicts.