Helicobacter pylori, a Gram negative bacterium that has colonized humans for millennia, has developed several strategies to survive in the hostile environment of the stomach mucosa, thus causing chronic infection. Amongst these is the ability to overcome the first line of defense represented by macrophages, with which H. pylori comes into contact once the epithelial barrier is crossed. All strains are phagocytosed by macrophages. However, while type II strains (which lack the cag pathogenicity island and do not produce an active vacuolating cytotoxin) are efficiently killed, ulcerogenic type I strains not only retard their uptake but, most importantly, interfere with the physiological phagosome maturation by preventing the fusion of H. pylori-containing phagosomes with lysosomes. The aim of this chapter is to outline, step by step, the molecular mechanisms by which the most virulent bacterial strains are able to create a protective niche in which to survive inside macrophages. The crucial role of some H. pylori virulence factors in interfering at specific stages of phagosome maturation is also outlined.