Fire blight, a devastating disease caused by the bacterium Erwinia amylovora, is a major threat to apple crop production. To improve our understanding of the fire blight disease and to identify potential strategies to control the pathogen, we studied the apple protein HIPM (for HrpN-interacting protein from Malus spp.), which has previously been identified as interacting with the E. amylovora effector protein HrpN. Transgenic apple plants were generated with reduced HIPM expression, using an RNA interference construct, and were subsequently analyzed for susceptibility to E. amylovora infection. Lines exhibiting a greater than 50% silencing of HIPM expression showed a significant decrease in susceptibility to E. amylovora infection. Indeed, a correlation between HIPM expression and E. amylovora infection was identified, demonstrating the crucial role of HIPM during fire blight disease progression. Furthermore, an apple oxygen-evolving enhancer-like protein (MdOEE) was identified via a yeast two-hybrid screen to interact with HIPM. This result was confirmed with bimolecular fluorescence complementation assays and leads to new hypotheses concerning the response mechanism of the plant to E. amylovora as well as the mechanism of infection of the bacterium. These results suggest that MdOEE and, particularly, HIPM are promising targets for further investigations toward the genetic improvement of apple.