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Immune system responsiveness results from numerous factors, including endogenous cannabinoid signaling in immunocytes termed the “immunocannabinoid” system. This system can be an important signaling pathway for immune modulation. To assess the immunomodulating role of the cannabinoid 2 (CB2) receptor, we sought polymorphisms in the human gene, identified a common dinucleotide polymorphism, and investigated its effect on endocannabinoid-induced inhibition of T lymphocyte proliferation. The CB2 cDNA 188–189 GG/GG polymorphism predicts the substitution of glutamine at amino acid position 63 by arginine. T lymphocytes from CB2 188–189 GG/GG homozygotes had approximately twofold reduction of endocannabinoid-induced inhibition of proliferation compared with cells from CB2 188–189 AA/AA homozygotes. In GG/GG subjects, the reduced endocannabinoid inhibitory response …