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The purpose of this study was to evaluate risk factors for nonunion after femoral nailing of femoral shaft fractures. A case-control study with two to one matching was conducted. Forty-five patients with 46 femoral nonunions (cases) and 92 patients with healed femoral shaft fractures (controls) were identified from our orthopedic trauma registry. All cases and controls were initially managed with reamed, statically locked femoral nails. The characteristics that were significantly different between the two groups were open fracture, delay to weight bearing, and tobacco use. Fracture classification, gender, direction of nail insertion (antegrade vs. retrograde), and Injury Severity Score were not predictive of nonunion. We conclude that open fracture, tobacco use, and delayed weight bearing are risk factors for femoral nonunion after intramedullary nailing for diaphyseal femur fractures.