The incidence of neurologic injury after proximal humerus fractures is variable, ranging from 6.2% to as much as 67%. However, it is unclear what factors might contribute to these injuries or whether they can be prevented by intraoperative nerve monitoring. Therefore, using intraoperative nerve monitoring, we assessed the incidence, pattern of nerve involvement, and predisposing factors for nerve injury before and during shoulder fracture fixation. We used continuous intraoperative monitoring of the brachial plexus in 37 patients undergoing open operative treatment of proximal humerus fractures. Impending intraoperative compromise of nerve function was signaled by sustained neurotonic EMG activity or greater than 50% amplitude attenuation of transcranial electrical motor evoked potentials (MEPs) (or both). When a nerve alert occurred, current surgical activity and arm and retractor position were recorded and adjustments were made to relieve tension. The intraoperative affected nerves included axillary (46%), combined (mixed plexopathy) (23%), radial (23%), musculocutaneous (4%), and ulnar (4%). Postoperatively, three patients had transient nerve palsies, which fully resolved within 3 weeks of surgery. Low body mass index (BMI) (22.7 ± 2.8), history of cervical spine disease, diabetes mellitus, and delay in surgical treatment (14 ± 2.9 days from time of injury) were associated with an increased incidence of nerve dysfunction. Our observations suggest transcranial electrical MEPs are sensitive indicators of impending iatrogenic injury to the brachial plexus or peripheral nerves (or both) during open operative treatment of proximal humerus fractures. The use of intraoperative nerve monitoring during these procedures may be considered for the prevention of nerve injury, particularly in patients with underlying cervical spine disease, low BMI, diabetes mellitus, and/or delay in surgical treatment greater than approximately 14 days. Level III, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.