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The suprapatellar approach for medullary nailing of the tibia is increasing. This requires intra-articular passage of instruments, which theoretically places the knee at risk of postoperative sepsis in the setting of open fracture. We hypothesized that the risk of knee sepsis is similar after suprapatellar or infrapatellar nailing of open tibia fractures.Retrospective, multicenter.Three urban level 1 trauma centers.All patients treated with medullary nailing for open diaphyseal tibia fractures (OTA 42) from 2009 to 2015. Patients younger than 18 years of age and with less than 12 weeks of follow-up were excluded. We identified 289 fractures in 282 patients.Suprapatellar (SP) or infrapatellar (IP) medullary nailing of open tibia fractures.Occurrence of ipsilateral knee sepsis, defined as presence of a positive culture from knee aspiration or arthrotomy. Deep infection requiring operative debridement, superficial infection requiring antibiotic therapy alone, and all-cause reoperation were also recorded.IP nailing was used for 142 fractures. There were 20 infections (14.1%), of which 14 (9.8%) were deep. Fourteen tibias (9.8%) required reoperation for noninfectious reasons for 28 total reoperations (19.7%). SP nailing was used in 147 fractures. There were 24 infections (16.2%), of which 16 (10.8%) were deep. Fourteen additional tibias (9.5%) required reoperation for noninfectious reasons for a total of 30 reoperations (20.4%). There were no differences in the rates of infection, deep infection, or reoperation between groups. There were 2 cases of knee sepsis after SP nailing (1.4%) but zero cases after IP nailing (P = 0.5).There was no significant difference in the rate of knee sepsis with SP or IP approaches. The risk of knee sepsis after SP nailing of open fractures is low, but present.Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.