The supra-patellar approach represents one approach to intramedullary nailing (IMN) of diaphyseal tibia fractures. Violation of the knee joint utilizing an intra-articular start point represents a risk for septic arthritis of the knee in the post-operative period. Previous retrospective studies of open tibia and femur fractures demonstrated that post-operative knee sepsis is rare, occurs in the chronic phase after injury, and due to extent of soft tissue injury rather than immune compromise. Here, we review current literature on post-operative knee sepsis, and present a case of acute septic arthritis of the knee following supra-patellar nailing of an open tibia fracture in a patient on chronic immune suppression. In this unique case, co-morbid patient factors likely led to this manifestation of a rare complication.