Helicobacter pyloriis a gastric pathogen responsible for a high disease burden worldwide. Deregulated inflammatory responses, possibly involving macrophages, are implicated inH.pylori-induced pathology, and microRNAs, such as miR-155, have recently emerged as crucial regulators of innate immunity and inflammatory responses. miR-155 is regulated by Toll-like receptor (TLR) ligands in monocyte-derived cells and has been shown to be induced in macrophages duringH.pyloriinfection. Here, we investigated the regulation of miR-155 expression in primary murine bone marrow-derived macrophages (BMMs) duringH.pyloriinfection and examined the downstream mRNA targets of this microRNA using microarray analysis. We report TLR2/4- and NOD1/2-independent up-regulation of miR-155, which was found to be dependent on the majorH.pyloripathogenicity determinant, the type IV secretion system (T4SS). miR-155 expression was dependent on NF-κB signaling but was independent of CagA. Microarray analysis identified known gene targets of miR-155 in BMMs duringH.pyloriinfection that are proapoptotic. We also identified and validated miR-155 binding sites in the 3′ UTRs of the targets,Tspan14,Lpin1, andPmaip1. We observed thatH.pylori-infected miR-155−/−BMMs were significantly more susceptible to cisplatin DNA damage-induced apoptosis than were wild-type BMMs. Thus, our data suggest a function for the prototypicalH.pyloripathogenicity factor, the T4SS, in the up-regulation of miR-155 in BMMs. We propose the antiapoptotic effects of miR-155 could enhance macrophage resistance to apoptosis induced by DNA damage duringH.pyloriinfection.