Mid-distal third humeral shaft fractures can be effectively treated with minimally invasive plating osteosynthesis and intramedullary nailing (IMN). However, these 2 treatments have not been adequately compared. Forty-seven patients (47 fractures) with mid-distal third humeral shaft fractures were randomly allocated to undergo either minimally invasive plating osteosynthesis (n=24) or IMN (n=23). The 2 groups were similar in terms of fracture patterns, fracture location, age, and associated injuries. Intraoperative measurements included blood loss and operative time. Clinical outcome measurements included fracture healing, radial nerve recovery, and elbow and shoulder discomfort. Radiographic measurements included fracture alignment, time to healing, delayed union, and nonunion. Functional outcome was satisfactory in both groups. Mean American Shoulder and Elbow Surgeons score and Mayo score were both better for the minimally invasive plating osteosynthesis group than for the IMN group (98.2 vs 97.6, respectively, and 93.5 vs 94.1, respectively; P<.001). Operative time was shorter and less intraoperative blood loss occurred in the minimally invasive plating osteosynthesis group than in the IMN group. Average time to union was similar in both groups. Primary union was achieved in 23 of 24 patients in the minimally invasive plating osteosynthesis group and in 22 of 23 in the IMN group. Minimally invasive plating osteosynthesis may have outcomes comparable with IMN for the management of mid-distal third humeral shaft fractures. Minimally invasive plating osteosynthesis is more suitable for complex fractures, especially for radial protection and motion recovery of adjacent joints, compared with IMN for simple fractures.