Controversy exists on the relationship between intramedullary nailing (IMN) and the timing of fixation in the development of respiratory failure (RF) following femoral fractures. The purpose of this study is to identify risk factors for RF and evaluate the role of multiple IMN in the above setting. We prospectively observed 126 consecutive patients with femoral fractures for the development of RF. Twenty-one patients (17%) developed RF. This occurred before fracture fixation in 11 patients and after IMN in 10 patients; five after multiple IMN and five after a single IMN procedure. Patients who underwent multiple IMN demonstrated a significant increase of RF after fracture fixation (5/8,) compared to patients with one IMN procedure (5/114, 4.4%, p<0.001). Stepwise regression analysis identified two independent RF risk factors: thoracic injury and multiple IMN (odds ratios: 40.6 and 25.6, respectively). Thoracic injury and multiple IMN procedures are independent risk factors for RF in patients with femoral fractures, and the combination of the above conditions is highly predictive of the development of RF.