The microaerophilic Gram-negative bacterium, Helicobacter pylori, causes chronic gastritis, peptic ulcers, and gastric cancer in humans. Although the luminal surface of the gastric epithelium is the primary site of persistent colonisation by H. pylori, recent data suggests that H. pylori can gain access to deeper tissue. Indeed, presence of H. pylori in the vicinity of endothelial cells (ECs) in the stomach has been reported. ECs play crucial roles in wound healing, innate immune response and tumorigenesis. A potential link between H. pylori infection and angiogenesis has been proposed. In this study, we aimed to investigate the molecular mechanisms underlying the interaction of H. pylori with primary human ECs. Using human umbilical vein endothelial cells (HUVECs) as a model, we observed that infection of primary ECs by H.pylori at a multiplicity of infection (MOI) of 1 was sufficient to trigger a 10-fold induction of the potent chemokine, interleukin-8 (IL-8). This response was significantly stronger than that observed with the human gastric epithelial cell line, AGS, arguing for an equally if not more important role of ECs in H. pylori-mediated inflammatory responses. In contrast, minimal IL-8 induction was observed with an isogenic H. pylori mutant that lacks the type IV secretion system. Furthermore, neither CagA, a protein substrate of the type IV secretion system, nor the coupling protein VirD4, which is essential for the translocation of type IV substrates, contributed to the induction of IL-8 in HUVECs. These findings suggest that the type IV secretion apparatus per se is a previously unrecognised, important trigger of proinflammatory response in infected primary ECs. Given that IL-8 is also a potent inducer of angiogenesis and tumorigenesis, our study provides novel evidence supporting the hypothesis that H.pylori might promote gastric carcinogenesis partly through the modulation of endothelial functions.