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Retrograde nailing of open femoral fractures has presumed increased risk of knee sepsis. Our hypothesis was that the incidence of secondary knee infection after retrograde nailing of open femoral fractures is low.Retrospective, multicenter.Four Level I trauma centers.A retrospective review of prospective trauma registries and fracture databases identified all open femoral fractures treated with retrograde intramedullary nailing from January 1, 2003, through February 15, 2007. Patients with ballistic injuries and those with less than 1 month follow up were excluded. Ninety-three open femoral fractures were identified in 90 patients. We defined a septic knee as a knee with infection that required reoperation with arthrotomy or arthroscopy. Infections at an open fracture site were defined as those treated with local irrigation and débridement and intravenously and/or orally administered antibiotics.Open femoral shaft fractures treated with a retrograde approach.Occurrence of an ipsilateral postoperative septic knee.One acute septic knee was identified (1.1%; 95% confidence interval, 0.0%-3.2%) noted at time of repeat irrigation and débridement of a massive degloving wound that left no skin coverage over the knee. We also observed one late knee sepsis 2.5 years after the index procedure occurring after quadricepsplasty. The nail had been removed 1.5 years before surgery, so we did not include that case in our knee sepsis rate. Two additional infections at the open wound site did not involve the knee.Previous publications have argued that retrograde nailing of open femoral fractures provides a potential conduit for knee infection. Our data show that risk of a septic knee as a direct result of retrograde nailing of an open femoral fracture is relatively low (1.1%; 95% confidence interval, 0.0%-3.2%). To our knowledge, this is the first case series to document the relative safety associated with retrograde nailing of open femoral fractures.