The purpose of this study was to investigate the immunomodulatory effect of delta-9-tetrahydrocannabinol (THC) on spleen and lymph node cells of adult and young mice. When plant mitogen (Con A or PHA) stimulated cells were treated with varying doses of THC, the proliferation of spleen and lymph node cells of adult and young mice was suppressed. This suppression was found to be compatible with a decrease in number of Tac positive cells as well as a down-regulation of IL-2 activity. In contrast, when these cells were stimulated with anti-CD3 antibody in combination with THC, the pattern of the immunomodulation as well as the absolute effects of the drug differed with the age of the mice as well as the organ of origin of the cells. In this regard, anti-CD3 antibody stimulation in combination with low doses of THC stimulated proliferation of splenocytes obtained from adult mice. The stimulation was found to reflect an increase in the number of both suppressor/cytotoxic T cells (Ly2 cells) as well as Tac positive cells. IL-2 activity was found to be enhanced under these conditions. This up-regulation of responsiveness was not seen in either lymph node cells of adult or young mice or in spleen cells of young mice. The THC modulating activity is directly related to its effect on both IL-2 activity and generation of Tac positive cells in spleen and lymph node cells of both adult and young mice. It appears, therefore, that not only age, but also lymphoid organ system differences are important factors in terms of considering the effects of drugs of abuse.