This paper deals with the influence of local plastic deformation on the fatigue strength of holed plates manufactured with an innovative medium-carbon micro-alloyed steel with high silicon content (hi-Si MCM). Local deformation around the hole is achieved by means of an interference fitted pin. The effect was investigated both experimentally and numerically. Microstructural characterization, hardness, and tensile tests were carried out first. Tension–tension fatigue tests were performed under two different conditions: open-hole (OH) specimens and specimens with a press fitted pin with 0.6% nominal specific interference. A 2D elastic–plastic finite element analyses (FEAs) investigation was done as well, in order to analyze the stress field in the vicinity of the hole. The stress history and distribution in the neighborhood of the hole indicate a significant reduction of the stress amplitude produced by the external loading (remote stress) when a residual stress field is generated by the pin insertion. In fact, experimental stress-life (SN) curves pointed out increased fatigue strength of the interference fit specimens, compared with the OH ones. Finally, scanning electron microscope (SEM) analyses of the fractured fatigue specimens were carried out, in order to investigate the mechanisms of failure and to relate them to the peculiar microstructural features that characterize this innovative steel.