The aim of this study was to identify risk factors for failure of exchange nailing for femoral diaphyseal fracture non-unions. The study cohort comprised 40 patients with femoral diaphyseal non-unions treated by exchange nailing, of which six were open injuries. The median time to exchange nailing from primary fixation was 8.4 months. The main outcome measures were union, number of secondary fixation procedures required to achieve union and time to union. Multiple causes for non-union were found in 16 (40%) cases, with infection present in 12 (30.0%) patients. Further surgical procedures were required in nine (22.5%) cases, one of whom (2.5%) required the use of another fixation modality to achieve union. Union was ultimately achieved with exchange nailing in 34/37 (91.9%) patients. The median time to union after the exchange nailing was 9.4 months. Cigarette smoking and infection were risk factors for failure of exchange nailing. Multivariate analysis found infection to be the strongest predictor of exchange failure (p< 0.05). Exchange nailing is an effective treatment for aseptic femoral diaphyseal fracture non-union. However, 50% of patients undergoing exchange nailing in the presence of infection required at least one further procedure. It is important to counsel patients of this so that they can plan for it and do not consider that the first exchange operation has failed.