Introduction Surgical site infection (SSI) is among the most common healthcare-related infections. Given their greater morbidity and surgical complexity, patients undergoing major surgery are exposed to a high risk of SSI. Objective To determine the incidence of SSI in adult patients undergoing major elective non-cardiac surgery, and to identify risk factors associated with its occurrence within the first 30 days after surgery. Methods An analytical study was designed on the basis of a prospective institutional registry. Clinical and laboratory variables associated with perioperative management were recorded. An active search was conducted in order to find SSI episodes, renal failure and multiple organ dysfunction during the first 30 days after surgery. Adjusted logistic regression was done to identify potential associations between risk factors and the development of SSI. Results Overall, 1501 patients were included. The incidence of SSI during the first 30 days after surgery was 6.72% (95% CI 5.57-8.11). ASA III, abdominal surgery and longer procedures were more frequent in the SSI group. Association with the occurrence of SSI was documented for preoperative hemoglobin levels (adjusted OR 0.79 [95% CI 0.72-0.88], p = 0.04), intraoperative transfusion (adjusted OR 2,47 [95% CI 1.16-5.27], p = 0.02) and major blood loss (adjusted OR 3.80 [95% CI 1.63-8.88], p = 0.04). Conclusion Preoperative hemoglobin level, intraoperative transfusion and major bleeding are independent risk factors associated with the occurrence of SSI in adult patients undergoing major elective non-cardiac surgery.