OBJECTIVES (1) To determine the infection rate after fixation of open tibial shaft fractures using the Surgical Implant Generation Network (SIGN) intramedullary nail in low- and middle-income countries (LMICs) and (2) to identify risk factors for infection. DESIGN Prospective cohort study using an international online database. SETTING Multiple hospitals in LMICs worldwide. PATIENTS/PARTICIPANTS A total of 1061 open tibia fractures treated with the SIGN nail in LMICs between March 2000 and February 2013. INTERVENTION Intravenous antibiotic administration, surgical debridement, and definitive intramedullary nailing within 14 days of injury. MAIN OUTCOME MEASUREMENTS Deep or superficial infection at follow-up, implant breakage/loosening, angular deformity >10 degrees, repeat surgery, radiographic union, weight bearing, and ability to kneel. RESULTS The overall infection rate was 11.9%. Infection rates by the Gustilo and Anderson classification were type 1: 5.1%, type II: 12.6%, type IIIa: 12.5%, type IIIb: 29.1%, and type IIIc: 16.7% (P = 0.001 between groups). Patients who developed infection had a longer mean time from injury to definitive surgery (4.7 vs. 3.9 days, P = 0.03) and from injury to wound closure (13.7 vs. 3.6 days, P < 0.001). Distal fractures had a higher infection rate than midshaft fractures (13.3% vs. 8.2%, P = 0.03). Infection rates were not associated with time from injury to initial debridement, time from injury to initial antibiotic administration, or total duration of antibiotics. CONCLUSIONS Open tibia fractures can be managed effectively using the SIGN intramedullary nail in LMICs with an overall infection rate of 11.9%. Risk factors for infection identified include more severe soft-tissue injury, delayed nailing, delayed wound closure, and distal fracture location. LEVEL OF EVIDENCE Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.