Acute exposure to morphine has been shown to inhibit phagocytosis in murine macrophages, whereas chronic exposure results in apparent desensitization. We now show that morphine may be either inhibitory or stimulatory depending on concentration and exposure time. Furthermore, under some conditions drug withdrawal from putatively desensitized cells will result in inhibition of phagocytosis, suggesting that a state akin to dependence has developed. Desensitization can also develop with intermittent exposures if the opiate-free period between drug exposures is shorter than 4 h. These effects of morphine on macrophages are important in understanding the role of this drug as an immunomodulatory agent.