Animal models are valuable tools for investigating the in vivo pathogenesis of Staphylococcus epidermidis infections. Here, we present the procedure for generating a central nervous system catheter-associated infection in a mouse, to model the central nervous system shunt infections that frequently complicate the treatment of hydrocephalus in humans. This model uses stereotactic guidance to place silicone catheters, pre-coated with S. epidermidis, into the lateral ventricles of mice. This results in a catheter-associated infection in the brain, with concomitant illness and inflammation. This animal model is a valuable tool for evaluating the pathogenesis of bacterial infection in the central nervous system, the immune response to these infections and potential treatment options.