ObjectiveTo compare the effectiveness of lateral approach minimally invasive plate osteosynthesis (MIPO) and helical plate MIPO in the treatment of proximal humeral shaft fractures. Methods The clinical data of patients with proximal humeral shaft fractures who underwent MIPO via lateral approach (group A, 25 cases) and MIPO with helical plate (group B, 30 cases) between December 2009 and April 2021 were retrospectively analyzed. There was no significant difference in gender, age, injured side, cause of injury, American Orthopaedic Trauma Association (OTA) fracture classification, and time from fracture to operation between the two groups (P>0.05). The operation time, intraoperative blood loss, fluoroscopy times, and complications were compared between two groups. The angular deformity and the fracture healing were evaluated according to anteroposterior and lateral X-ray films postoperatively. The modified University of California Los Angeles (UCLA) score for shoulder and the Mayo Elbow Performance (MEP) score for elbow were analyzed at last follow-up. Results The operation time in group A was significantly shorter than that in group B (P<0.05). However, the intraoperative blood loss and fluoroscopy times presented no significant difference between the two groups (P>0.05). All patients were followed up 12-90 months, with an average of 19.4 months. There was no significant difference in follow-up time between the two groups (P>0.05). In terms of the quality of postoperative fracture reduction, there were 4 (16.0%) and 11 (36.7%) patients with angulation deformity in group A and group B, respectively, and there was no significant difference in the incidence of angulation deformity (χ2=2.936, P=0.087). All fractures achieved bony union, there was no significant difference in fracture healing time between group A and group B (P>0.05); delayed union occurred in 2 cases and 1 case in group A and group B, respectively (healing time was 30, 42, and 36 weeks after operation, respectively). In group A and group B, 1 patient had superficial infection of incision, respectively; 2 patients and 1 patient had subacromial impact after operation, respectively; and 3 patients in group A had symptoms of radial nerve paralysis of different degrees; all of them were cured after symptomatic treatment. The overall complication incidence of group A (32%) was significantly higher than that of group B (10%) (χ2=4.125, P=0.042). At last follow-up, there was no significant difference in the modified UCLA score and MEPs score between the two groups (P>0.05). Conclusion Both lateral approach MIPO and helical plate MIPO can achieve satisfied effectiveness in the treatment of proximal humeral shaft fractures. Lateral approach MIPO may be beneficial to shorten the operation time, while the overall complication incidence of helical plate MIPO is lower.