Objective To compare the clinical efficacy and prognosis between classical infra-patellar (IP) and supra-patellar (SP) intramedullary nailing in the treatment of tibial shaft fractures. Methods A retrospective analysis was conducted of the 68 patients with tibial shaft fracture who had been treated from June 2012 to December 2014 and completed follow-ups. They were 59 males and 9 females, 18 to 87 years of age (mean, 43.7 years). Of them, 38 were treated through the SP approach and 30 through the IP approach. The 2 groups were compared in terms of surgery-related indexes, The Hospital for Special Surgery (HSS) knee function score and Johner-Wruhs evaluation for clinical efficacy at 1, 3, 6, and 9 months postoperation. The 2 groups showed no significant differences regarding preoperative general data (P>0.05). Results The 68 patients obtained an average follow-up of 6 months (range, from 1 to 9 months). Intra-operative accumulative fluoroscopy time in the IP group (2.1±1.1 s) was significantly less than in the SP group (3.3±1.8 s) (P<0.05). The number of limited open reduction (1) , intra-operative bleeding volume (128.6±164.1 mL) and number of second intra-operative shifting (4) in the SP group were significantly smaller than in the IP group (7, 216.2±195.9 mL and 10, respectively) (P<0.05). The HSS score in the SP group at 9 months (80.8±7.5 points) was significantly higher than in the IP group (74.0±5.4 points) (P<0.05). The clinical good to excellent rate at 9 months for the SP group (97.4%) was significantly higher than for the IP group (70.0%) (P<0.05). There were also significant differences between the 2 groups in postoperative adverse events like knee pain (P<0.05). No wound infection, limb shortening, internal fixation loosening or rupture, fracture nonunion or mal-union happened in either of the 2 groups. Conclusions In the treatment of tibial shaft fractures with intramedullary nailing, the supra-patellar surgical approach may effectively reduce the incidence of postoperative knee pain so that it can prevent degenerative changes of the knee joint in the long term. It may also lower the incidence of intraoperative second shifting. It also has the advantages of limited incision, simplicity, and limited scaring. In short, it may be superior to the classical infra-patellar approach. Key words: Tibial fractures; Knee joint; Treatment outcome; Infra-patellar approach; Supra-patellar approach