Background: organ-space surgical site infections (SSI) are the most serious and costly infections after colorectal surgery. Most previous studies of risk factors for SSI have analysed colon and rectal procedures together. The aim of the study was to determine whether colon and rectal procedures have different risk factors and outcomes for organ-space SSI. Methods: a multicentre observational prospective cohort study of adults undergoing elective colon and rectal procedures at 10 Spanish hospitals from 2011 to 2014. Patients were followed up until 30 days post-surgery. Surgical site infection was defined according to the Centers for Disease Control and Prevention criteria. Oral antibiotic prophylaxis (OAP) was considered as the administration of oral antibiotics the day before surgery combined with systemic intravenous antibiotic prophylaxis. Results: of 3,701 patients, 2,518 (68%) underwent colon surgery and 1,183 (32%) rectal surgery. In colon surgery, the overall SSI rate was 16.4% and the organ-space SSI rate was 7.9%, while in rectal surgery the rates were 21.6% and 11.5% respectively (p < 0.001). Independent risk factors for organ-space SSI in colon surgery were male sex (Odds ratio -OR-: 1.57, 95% CI: 1.14-2.15) and ostomy creation (OR: 2.65, 95% CI: 1.8-3.92) while laparoscopy (OR: 0.5, 95% CI: 0.38-0.69) and OAP combined with intravenous antibiotic prophylaxis (OR: 0.7, 95% CI: 0.51-0.97) were protective factors. In rectal surgery, independent risk factors for organ-space SSI were male sex (OR: 2.11, 95% CI: 1.34-3.31) and longer surgery (OR: 1.49, 95% CI: 1.03-2.15), whereas OAP with intravenous antibiotic prophylaxis (OR: 0.49, 95% CI: 0.32-0.73) was a protective factor. Among patients with organ-space SSI, we found a significant difference in the overall 30-day mortality, being higher in colon surgery than in rectal surgery (11.5% vs 5.1%, p = 0.04). Conclusions: organ-space SSI in colon and rectal surgery has some differences in terms of incidence, risk factors and outcomes. These differences could be considered for surveillance purposes and for the implementation of preventive strategies. Administration of OAP would be an important measure to reduce the OS-SSI rate in both colon and rectal surgeries.