Background: Due to the epidemiologic transition, diseases requiring surgical intervention has increased globally which led to the increment of surgery related complications. Surgical site infections remain a major post-operative complication even in hospitals with most modern facilities and standard protocols of preoperative preparation. The incidence of SSI in low-income countries is two times higher than that of middle and high-income countries. Though, Debre Tabor General Hospital has been providing surgical services there is no data on the incidence and predictors of surgical site infection. Objective: To determine the incidence and predictors of postoperative surgical site infections in patients having major surgeries at Debre Tabor General Hospital. Methods: A hospital-based prospective cohort study was conducted on 250 postoperative patients who had undergone major surgery from 10th, June 2018 to 10th, December, 2018. Patients were enrolled consecutively until the sample size is reached. Patients were followed for ten consecutive days and data were collected through patient interview, medical record review and direct observation. Data were coded, entered, cleaned, and, analyzed using SPSS 23.0 STATA 14.0 and Weibull’s parametric survival modeling was done to identify independent predictors. Kaplan Meier’s curve was done to compare survival between groups. Results: A total of 250 patients were followed for an average durations of 8.2 ± 2.8 days and produced 2041patient days of follow up. Forty-nine patients developed surgical site infection during this period. Incidence density of surgical site infection was 24 new cases per 100 patient days of observation. Duration of surgery (AHR= 4.07 95% confidence interval (CI): 1.28, 14.91), level of wound contamination (AHR= 13.83, 95% CI: 2.51, 76.35), anemia (AHR= 3.29 95% CI: 1.52, 7.12), and cancer (AHR=10.89, 95%CI: 2.47, 48.14) were independent predictors of postoperative surgical site infection in major surgery patients. Conclusions and Recommendations: The incidence rate of surgical site infection is high in the surgical ward of Debre Tabor General Hospital. Surgical team shall focus on maximizing their skill in order to shorten duration of surgery and reduce wound contamination. The SSIs surveillance system should also be strengthened to detect areas of improvement. Keywords- Major surgery, s