We recently reported that the GG genotype of the interleukin- 6 (IL- 6)- 174G > C promoter polymorphism is associated with clinical presentation of intracranial hemorrhage in brain arteriovenous malformation (AVM) patients. In this study, we investigated whether tissue IL- 6 expression was associated with IL- 6- 174G > C genotype, and whether IL- 6 was linked to downstream targets involved in angiogenesis and vascular instability. Our results showed that the highest IL- 6 protein levels in brain AVM tissue were associated with IL- 6- 174GG genotype (GG: 57.7 ± 20.2; GC: 35.6 ± 26.6; CC: 13.9 ± 10.2 pg/mg; p = 0.001). IL- 6 protein levels were increased in AVM tissue from patients with hemorrhagic presentation compared with patients without hemorrhage (55 ± 22 vs 40 ± 27 pg/mg; p = 0.038). IL- 6 messenger RNA expression strongly correlated with messenger RNA levels of IL- 1β , tumor necrosis factor- α , IL- 8, matrix metalloproteinase- 3 (MMP- 3), MMP- 9, and MMP- 12. We further investigated the plausibility of IL- 6 being an upstream cytokine responsible for initiating the angiogenic cascade by cell culture and animal experiments. IL- 6 induced MMP- 3 and MMP- 9 expression and activity in mouse brain and increased proliferation and migration of cerebral endothelial cells. Together, our results suggest that the IL- 6 genotype associated with intracranial hemorrhage modulates IL- 6 expression in brain AVM tissue, which is consistent with the hypothesis that inflammatory processes induce angiogenic activity possibly contributory to brain AVM intracranial hemorrhage. We recently reported that the GG genotype of the interleukin-6 (IL-6) -174G> C promoter polymorphism is associated with clinical presentation of intracranial hemorrhage in brain arteriovenous malformation (AVM) patients. In this study, we investigated whether tissue IL- 6 expression was associated with IL- 6- 174G> C genotype, and whether IL- 6 was linked to downstream targets involved in angiogenesis and vascular instability. Our results showed that highest IL- 6 protein levels in brain AVM tissue were associated with IL - 6- 174GG genotype (GG: 57.7 ± 20.2; GC: 35.6 ± 26.6; CC: 13.9 ± 10.2 pg / mg; p = 0.001). IL- 6 protein levels were increased in AVM tissue from patients with hemorrhagic presentation compared with patients without hemorrhage (55 ± 22 vs. 40 ± 27 pg / mg; p = 0.038). IL-6 messenger RNA expression highly correlated with messenger RNA levels of IL-1β, tumor necrosis factor- α, IL- 8, matrix metalloproteinase-3 (MMP-3), MMP-9, and MMP- 12. We further investigated the plausibility of IL-6 being an upstream cytokine responsible for initiating the angiogenic cascade by cell culture and animal experiments. IL-6 induced MMP-3 and MMP-9 expression and activity in mouse brain and increased proliferation and migration of cerebral endothelial cells Together, our results suggest that the IL-6 genotype associated with intracranial hemorrhage modulates IL-6 expression in brain AVM tissue, which is consistent with the hypothesis that inflammatory processes induce angiogenic activity possibly contributory to brain AVM intracranial hemorrhage.