Background One of the challenge to manage long bone fracture is the risk of infection. Intramedullary nailing is the standard treatment of long bone shaft fractures. Infection from the surgical site during orthopedic management is posing postoperative burdens in different perspectives like patient perspectives and healthcare facilities. However, there is limited information on the magnitude of infection in Ethiopia after surgical implant generation network (SIGN) nailing in the treatment of long bone shaft fractures. Therefore, the current study aimed to assess the prevalence of infection in patients with long bone shaft fractures treated with surgical implant generation network (SIGN) nailing. Objective To assess prevalence of infection in patients with long bone shaft fractures treated with SIGN nailing at Felege Hiwot Referral Hospital from January 1, 2015, to December 31, 2018, Bahir Dar, Northwest, Ethiopia. Methods This was a retrospective study over a period of 4 years. SIGN surgical-related data, presence or absence of infection from the documented information were collected from the chart/the source. The types of infection were also collected with the standard classification as superficial, deep and deep with osteomyelitis. Age, sex, fracture pattern, nature of fracture, mechanism of injury, prophylaxis antibiotics, nail type, follow-up in weeks and other factors were also extracted from the patients’ charts with structured checklist. Data were analyzed with statistical package for social sciences (SPSS) version 23. The analyzed data were presented with texts, tables and a graph. Results Three hundred and eighty-two long bone fractures were treated by locked SIGN intramedullary nailing during the study period. After screening the inclusion criteria, a total of 311 cases were included in this study. A total of 13 (4.2%) patients who treated with SIGN intramedullary nailing developed infection. Conclusions We conclude that the overall prevalence of infection with SIGN intramedullary nailing is almost similar with the surgeries done in the developed countries.