Background: Dextromethorphan (DXM) is a synthetic opioid analogue, similar to codeine that has antitussive effect but no opiate-like analgesic activity. It is widely used as an over-the-counter cough suppressant available in various cough and cold preparations; it is one of the often overlooked types of substance abuse by adolescents and young adults in the United States and around the world. So, the present study aims to investigate the side effects of the DXM abuse (sub-chronic and lethal doses) on the immune functions in rats.  Material and Methods: The rats were divided into three equal groups, the first one served as control, and the second and third were treated. Treated groups received oral doses of DXM which increasing per 10 days (double dose) for a month. Results We examined the sub-chronic and lethal effects of DXM administration on the cellular immune responses in rats. T cell stimulator, Phytohemagglutinin showed a significant suppress on lymphocytes  of peripheral blood proliferation and a highly significant decrease  on phagocytic and killing of S. aureusby PMN and macrophage cells. Moreover, it induced a significant decrease in serum IL-6, andIFN-γ levels, but, it exhibited a highly significant increase in serum IL-10 level throughout the period of experiment. In addition, it induced also a significant decrease in the production of cortisol during the experimental time except the last period of treatment in the 3^rd group, where, serum cortisol level gradually return to normal level. Conclusion: These results suggest that sub-chronic and lethal doses of DXM administration in rats disturbed cellular immune responses, exhibited potent anti-inflammatory actions, suppressed of leukocytes dependent production of cytokines such as IL-6 and IFN-γ. Moreover, it has some effects on serum cortisol concentration presumably via blockade of NMDA receptors.