Patients undergoing colorectal surgery (CRS) are known to be at increased risk of surgical site infection (SSI). We assessed the effect of diabetes and other risk factors on SSI in patients undergoing CRS and patients undergoing general surgery (GS). American College of Surgeons National Surgical Quality Improvement Program Participant Use Data File from 2005 to 2006 was used. Chi2 tests, t tests, and logistic regression were used to assess the risk factors. Of the 129,909 study patients 10.1 per cent were patients undergoing CRS. The incidence of SSI in patients undergoing CRS was 3.8 times higher (95% CI, 3.6-4.1) than in patients undergoing GS. The incidence of SSI was higher in diabetics than nondiabetics in patients undergoing CRS (15.4 vs. 11.0%, P < 0.001) and patients undergoing GS (5.3 vs. 3.1%, P < 0.001). The significant univariate predictors of SSI for patients undergoing GS and patients undergoing CRS were: males, American Society of Anesthesiologists (ASA) class, diabetes emergency surgery, operation time, and greater than 2 units of intraoperative red blood cell transfusion. For patients undergoing GS, increasing age was also significant. After multivariate adjustment, significant predictors of SSI for patients undergoing GS and patients undergoing CRS were: male gender, diabetes, ASA class, emergency surgery, and operation time. For patients undergoing GS, age also remained significant. Among patients undergoing CRS, insulin-dependent diabetes mellitus (IDDM) and noninsulin-dependent diabetes mellitus (NIDDM) were 1.32 (P < 0.05) times more likely than nondiabetics to develop SSI. Among patients undergoing GS, only IDDM (OR, 1.39; P < 0.001) were at increased risk. In this large hospital-based study, patients undergoing CRS were three times more likely to get SSI than patients undergoing GS. Diabetic patients with CRS (IDDM and NIDDM) and patients undergoing GS (IDDM) were at increased risk of SSI compared with nondiabetics. More intense glycemic control may reduce SSI in patients undergoing CRS with diabetes.