This study examined the immunoregulatory effects of anadamide, the recently identified first endogenous cannabinoid receptor ligand. Anadamide caused dose-dependent inhibition of mitogen-induced T and B lymphocyte proliferation. Its potency was 3- and 10-fold less than that of the synthetic cannabinoids delta 8-tetrahydrocannabinol (delta 8-THC) and CP55940, respectively. Anadamide effects on DNA synthesis in T and B lymphocytes occurred rapidly as exposure of the cells during the final 4 h of culture was sufficient to achieve > 40% inhibition. Low doses of anadamide which caused significant inhibition of lymphocyte proliferation caused DNA fragmentation as demonstrated by immunohistochemistry, FACS analysis and Southern blotting. Apoptosis was also induced by high concentrations of delta 8-THC, but not by CP55940. Brain and peripheral cannabinoid receptor mRNA was expressed in PBMC with varying levels between individual donors. In summary, these findings demonstrate immunosuppressive effects of anadamide which are associated with inhibition of lymphocyte proliferation and the induction of cell death by apoptosis.