Staphylococcus epidermidis is one of the major causes of nosocomial infections in humans. This organism can exist as a commensal on the skin. However, it can also lead to severe infections. The immune system has evolved mechanisms to deal with microorganisms and has strategies to combat bacteria. The initial defense against S. epidermidis infections includes the activation of complement complex, recruitment and then killing of the microorganism by effectors. The success of pathogenic S. epidermidis strains has been attributed to their capacity to evade innate immune cells. Extracellular matrix binding protein, polysaccharide intercellular adhesin, and accumulation-associated protein have been found to suppress killing of S. epidermidis by effector cells. PSM constitutes the only kind of exported toxins in S. epidermidis strains and has strong cytolytic features against leukocyte cells. The human innate immune system can be stimulated against S. epidermidis via toll-like receptors that enhance antibacterial reactions, trigger inflammation, and result in the stimulation of immune system effectors, e.g., type-1 interferon (IFN-alpha and IFN-beta), proinflammatory cytokines, and nitric oxide. Proinflammatory cytokines, e.g., interleukin-1, interleukin-6, and tumor necrosis factor are formed from resident human cells and result in migration of the lymphocyte and fever. In this review we will examine the immune system's response against S. epidermidis.