OBJECTIVE To compare therapeutic effects between antegrade intramedullary nailing and retrograde intramedullary nailing for the treatment of humeral shaft fractures. METHODS From March 1999 to October 2006, 105 patients with humeral shaft fractures were treated with locked intramedullary nail and were adequately followed up. There were 82 antegrade nailing and 23 retrograde nailing. The follow-up parameters included operation time, blood loss,fracture healing rate, healing time, complications, Constant-Murley shoulder score and Mayo elbow performance score. RESULTS The mean follow-up period was 31.2 months. Antegrade intramedullary nailing had significantly less blood loss than that in retrograde intramedullary nailing (P=0.002). The differences in operation time, complications, healing time and bone healing rate between he two groups had no statistical significance. Complications in the antegrade intramedullary nail group included 4 patients with nonunions, 1 patient with radial nerve palsy, and 8 patients with shoulder pains and decrement in shoulder range of motion. Complications in the retrograde intramedullary nail group included 1 patient with radial nerve palsy and 3 patients with iatrogenic fractures. For shoulder joints,the difference in the average Constant-Murley shoulder score between the two groups was statistically significant (P=0.04). For elbow joints, the average postoperative Mayo elbow performance score between these two approaches did not differ significantly. CONCLUSIONS Both the antegrade intramedullary nailing and the retrograde intramedullary nailing are good alternatives for the treatment of humeral shaft fractures. Because of higher incidence of iatrogenic fractures, the insertion point of retrograde intramedullary nailing should be carefully prepared. With antegrade insertion, it important to bury the humeral nail below the rotator cuff to prevent the subacromial impingement, and the rotator cuff should be carefully repaired to avoid shoulder pain and improve shoulder function.