Intramedullary nailing (IMN) is an accepted technique for the treatment of humeral shaft fractures. Previous studies published concerns over whether this technique had higher complication rates such as nonunion and technical failures compared to plate osteosynthesis. We, therefore, conducted a single centre failure analysis to critically evaluate our results regarding IMN of humeral shaft fractures. Between January 2000 and January 2013, 246 consecutive patients with humeral shaft fractures were enrolled. Inclusion criteria were skeletal maturity and humeral shaft fractures treated with IMN. Exclusion criteria were skeletal immaturity, primary treatment by plate osteosynthesis, primary treatment outside the University Hospitals Leuven, presence of metaphyseal fractures and the presence of pathological fractures. Negative outcome measures such as infection, nonunion and early technical failure were retrospectively assessed. During the study period, 149 patients with 149 fractures met the inclusion criteria. Of these, 14 patients were lost to follow-up, two died from trauma-related causes within the first 30 days after the accident, and eight died from other causes (cardiovascular disease and cancer) leaving 125 patients with 125 fractures for a minimum follow-up period of 12 months. Failure analysis showed that six (4.8 %) patients developed a nonunion. One (0.8 %) patient was diagnosed with a deep infection. In total, five (5 %) patients underwent surgical revision due to early technical failures. IMN is a valid therapeutic option for humeral shaft fractures. Good surgical technique and soft tissue handling are important for good outcome. Currently, patient demands are receiving greater consideration. In an era where early full range of motion and rapid return to work with minimal scaring is mandatory for most patients, the use of IMN will most likely increase in popularity in the future.