The anterolateral (AL) and anteromedial (AM) surfaces of the humerus are typically used for plate placement during plate osteosynthesis of midshaft humeral fractures via the anterolateral approach. The purpose of this study was to determine if a significant difference exists in the rates of iatrogenic radial nerve palsy (IRNP) following either AL or AM humeral fracture plating. The research question is stated as follows: is anteromedial plating of humeral fractures associated with lower rates of IRNP when compared with anterolateral plating? This multicenter prospective randomized study was undertaken following ethical review and approval with eligible patients who had midshaft humeral fractures or nonunions randomized into 2 groups, viz AL plate osteosynthesis group and AM plate osteosynthesis group. Following diagnostic and preoperative evaluation, patients had open plate osteosynthesis through the anterolateral approach with plate placement according to their study groups. Post-operatively, they were assessed for IRNP while obtained data was analyzed with SPSS version 23 and inter-group differences with P values less than 0.05 were considered statistically significant. Eighty-five eligible patients participated in the study with 43 patients in Group A (AL plate osteosynthesis group) and 42 patients in Group B (AM plate osteosynthesis group). The observed inter-group differences with regard to gender distribution, mean age and clinical diagnosis; acute fracture (AF) versus nonunion were not statistically significant. Furthermore, four (9.3%) patients amongst the 43 patients in Group A (AL plate osteosynthesis group) developed IRNP while two (4.8%) patients amongst the 42 patients in Group B (AM plate osteosynthesis group) had IRNP. The inter-group difference with regard to rates of IRNP was not statistically significant (P = 0.694). This study found that (in contrast to previous studies) there was no significant difference in the rates of IRNP following either open anterolateral or anteromedial plate osteosynthesis of midshaft humeral fractures through the anterolateral approach. Orthopaedic surgeons should therefore remain cautious when obtaining consent for surgery as well as when performing internal fixation of midshaft humeral fractures to limit medicolegal disputes that may arise from IRNP.