Brain pathology is an important aspect of human sepsis but is difficult to study in human patients. Therefore, animal models of sepsis-related brain pathology are needed. As pigs mirror multiple aspects of sepsis-related brain pathology in humans, this makes the pig a potentially suitable model. Unfortunately, models of sepsis in pigs are difficult to manage due to the accompanying massive systemic inflammatory response. To overcome these difficulties we designed a model in pigs of brain bacteremia established by local brain infusion in order to evaluate if this approach could reduce the systemic responses but still reflect the brain pathology of sepsis in humans. As a pilot study to obtain basic knowledge, we evaluated two methods of local infusion: long term infusion (60 minutes) of Staphylococcus aureus suspended in saline and, short-term infusion (10 minutes) of S. aureus embedded in autologous microthrombi. The study revealed: 1) bacteria suspended in saline as well as embedded in microthrombi can pass through the rete mirabile and thereby cause local brain bacteremia; 2) despite the high dose of S. aureus used for infusion, only mild clinical signs developed; and 3) despite the mild clinical signs, one pig had developed a brain microabscess by 48 h after infusion. The brain pathology present in this pig thereby reflected human cases of S. aureus-sepsis with microabscess formation as the predominant lesion. In addition, the abscess morphology mirrored previously observed microabscesses in experimental porcine S. aureus sepsis models.