This multicentered randomized controlled trial enrolled 254 patients with OTA/AO type 42 and 43A tibial fractures treated with reamed intramedullary nailing. Patients were randomized to undergo either suprapatellar nailing or infrapatellar nailing. At two years, 96 patients in the suprapatellar group and 93 patients in the infrapatellar group completed the follow-up. The primary outcome was knee pain after kneeling for 60 seconds measured using a visual analog scale (VAS). Secondary outcomes included the Aberdeen Kneeling Test, Aberdeen Standing Test, Lysholm score, EQ-5D, and Work Productivity and Activity Impairment Questionnaire. Outcomes were assessed at 6 weeks, 4 months, 6 months, 1 year, and 2 years postoperatively. Overall, the results of the study revealed that suprapatellar nailing resulted in statistically lower knee pain scores at early and mid-term follow-up; however, these differences did not make a clinically important difference. Suprapatellar nailing was consistently associated with greater ability to bear weight through the operative knee during kneeling up to two years postoperatively. No clinically meaningful differences were observed in patient-reported outcome measures or complication rates.