Alpha 2 adrenergic receptors (α2 ARs) play a central role in the regulation of systemic sympathetic activity. Prejunctional alpha 2A adrenoceptor regulates through negative feedback at presynaptic nerve ending. A-1291 C>G polymorphism located in α2-adrenergic receptor gene (ADRΑ2A) has been identified. We investigated the possible association between 1291 C>G polymorphism in the promoter region of ADRΑ2A in clinical subtypes of IBS, ulcerative and microscopic colitis patients.This prospective case control study included 92 patients with diarrhea predominant IBS (D-IBS), 44 with constipation predominant IBS (C-IBS), 15 with alternating diarrhea and constipation IBS (M-IBS), 75 ulcerative colitis (UC), 41 microscopic colitis (MC) and 100 healthy controls. The subjects were genotyped by using PCR amplification of the promoter region of ADRΑ2A gene followed by digestion with the restriction enzyme MspI. The study was approved by the institute ethical committee.A strong genotypic association was observed between α2A-1291 C>G polymorphism and D-IBS (χ 2 =6.38, df=2, p<0.05). There was no significant difference in α2A-1291 C>G genotype and allele frequency between C-IBS, M-IBS, UC, MC cases and control subjects.A significant association was observed between α2A-1291C>G polymorphism and D-IBS. Thus, α2 AR gene may be a potential candidate involved in the pathophysiology of D-IBS.