BackgroundIntramedullary humeral nailing is a common and reliable procedure for the treatment of humeral shaft fractures. Radial nerve palsy is a common complication encountered in the treatment of this pathology. The radial nerve runs from posterior to anterior at the lateral aspect of the distal humerus. Hence, there is reason to believe that due to the anatomic vicinity of the radial nerve in this area, lateral–medial distal locking in intramedullary nailing of the humerus may be associated with a greater risk for iatrogenic radial nerve injury compared to anterior–posterior locking.Questions/purposeTo assess whether the choice of distal locking (lateral–medial versus anterior–posterior distal locking) in intramedullary humeral nailing of humeral shaft fractures affects the risk for iatrogenic radial nerve injury.Patients and methodsOverall, 203 patients (116 females, mean age 64.3 ± 18.6 years), who underwent intramedullary nailing of the humerus between 2000 and 2020 at a single level-one trauma center, met the inclusion criteria and were analyzed in this retrospective case–control study. Patients were subdivided into two groups according to the distal locking technique.ResultsAnterior–posterior locking was performed in 176 patients versus lateral–medial locking in 27 patients. We observed four patients with iatrogenic radial nerve palsy in both groups. Risk for iatrogenic radial nerve palsy was almost 7.5 times higher for lateral–medial locking (OR 7.48,p= 0.006). There was no statistically significant difference regarding intraoperative complications, union rates or revision surgeries between both groups.ConclusionsLateral–medial distal locking in intramedullary nailing of the humerus may be associated with a greater risk for iatrogenic radial nerve palsy than anterior–posterior locking. Hence, we advocate for anterior–posterior locking.Level of evidenceLevel III retrospective comparative study.