Plate and screw fixation (PSF) has always been the more common surgical treatment of humeral shaft fractures. However, intramedullary nailing (IMN) of the humerus has gained in popularity over the last two decades. The purpose of this retrospective study was to evaluate the clinical outcome of plate fixation versus intramedullary nailing of midshaft humeral fractures. The study included 91 patients treated at the department of Trauma Surgery of the University hospital of Leuven; 42 fractures had been treated by plate fixation and 49 by IM nailing. Union, functional outcome, possible complications and the need for additional surgery were compared between the IMN and PSF group. No significant difference in terms of fracture union and functional recovery was noted between the two groups. There were four cases of postoperative radial nerve palsy in the PSF group, versus two in the IMN group (non significant difference). A significantly larger number of patients with restrictive pain and/or functional hindrance in the shoulder or elbow was noted in the IMN group (p = 0.0053). Problems with osteosynthesis material occurred as often in the PSF group as in the IMN group. One patient developed wound infection at the shoulder after antegrade nailing. A significantly larger number of complications was seen in the IMN group than in the PSF group (p = 0.05). A reoperation was necessary in 143% of the PSF patients and 163% of the IMN patients (non significant difference). In this retrospective study, IMN did not achieve better results than PSF of humeral midshaft fractures and was associated with more postoperative complications. Based on these findings, we suggest that plating of humeral shaft fractures should be considered as the primary treatment for all surgical indications, except for some open fractures requiring temporary external fixation, pathological fractures, humeral shaft fractures in morbidly obese and osteopenic patients, and large segmental fractures of the humerus.