In spite of great advancements in the field of biomaterials and in surgical techniques, the implant of medical devices is still associated with a high risk of bacterial infection. Implant-associated osteomyelitis is a deep infection of bone around the implant. The continuous inflammatory destruction of bone tissues characterizes this serious bone infectious disease. Staphylococcus aureus and Staphylococcus epidermidis are the most prevalent etiologic agents of implant-associated infections, together with the emerging pathogen Staphylococcus lugdunensis. Various interactions between staphylococci, osteoblasts, and phagocytes occurring in the peri-prosthesis environment play a crucial role in the pathogenesis of implant-associated osteomyelitis. Here we focus on two main events: internalization of staphylococci into osteoblasts, and bacterial interactions with phagocytic cells.