Background The beta-2 adrenergic receptor (ADRB2) is an important target for epinephrine, a neurotransmitter in pain signalling. ADRB2 haplotypes affect receptor expression and ligand response, and have been linked to painful non-GI disorders. Aims To assess whether ADRB2 polymorphisms (rs1042713, rs1042714) are risk alleles for functional GI (FGID) and extraintestinal functional (EIFD) diagnoses, and whether ADRB2 predicts GI symptoms and health-related quality of life (HRQOL). Methods Of 398 subjects (49.6 ± 2.9 years, 68.0% female), 170 (42.5%) met Rome III criteria for ≥1 FGID [IBS (n = 139, 34.9%); functional dyspepsia (FD, n = 136, 34.1%), functional chest pain (FCP, n = 25, 6.2%)], while 228 were healthy controls. FGID subjects reported on bowel symptom severity and burden (10-cm VAS), frequency (days/last 2 weeks), EIFD, psychiatric diagnoses and HRQOL (SF 36). Multivariable models determined the contribution of ADRB2 polymorphisms to HRQOL, and mediational analyses assessed functional diagnoses as potential intermediates. Results rs1042714 minor G alleles were associated with FGID diagnoses (OR 1.8; 95% CI 1.2-2.7; P = 0.009), particularly FD (OR 2.1, 95% CI 1.3-3.3), with trends towards IBS (P = 0.19) and FCP (P = 0.06) diagnoses. Within IBS, G allele carriers had more severe bowel symptoms (P = 0.025), and symptomatic days (P = 0.009). G allele carriers had greater numbers of EIFD (1.0 ± 0.1 vs. 0.4 ± 0.07, P < 0.001) and poorer HRQOL. The effect of ADRB2 on HRQOL was partially mediated by FGID, EIFD and psychiatric diagnoses. Conclusions ADRB2 minor alleles at rs1042714 predict FGID and EIFD, and may influence bowel symptom severity and HRQOL. These findings provide indirect evidence of sympathetic nervous system role in FGID pathophysiology.