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Background. There are limited data on risk factors for surgical site infection (SSI) after open or laparoscopic cholecystectomy. Methods. A retrospective cohort of commercially insured persons aged 18-64 years was assembled using International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) procedure or Current Procedural Terminology, 4th edition codes for cholecystectomy from December 31, 2004 to December 31, 2010. Complex procedures and patients (eg, cancer, end-stage renal disease) and procedures with pre-existing infection were excluded. Surgical site infections within 90 days after cholecystectomy were identified by ICD-9-CM diagnosis codes. A Cox proportional hazards model was used to identify independent risk factors for SSI. Results. Surgical site infections were identified after 472 of 66 566 (0.71%) cholecystectomies; incidence was higher after open (n = 51, 4.93%) versus laparoscopic procedures (n = 421, 0.64%; P < .001). Independent risk factors for SSI included male gender, preoperative chronic anemia, diabetes, drug abuse, malnutrition/weight loss, obesity, smoking-related diseases, previous Staphylococcus aureus infection, laparoscopic approach with acute cholecystitis/obstruction (hazards ratio [HR], 1.58; 95% confidence interval [CI], 1.27-1.96), open approach with (HR, 4.29; 95% CI, 2.45-7.52) or without acute cholecystitis/obstruction (HR, 4.04; 95% CI, 1.96-8.34), conversion to open approach with (HR, 4.71; 95% CI, 2.74-8.10) or without acute cholecystitis/obstruction (HR, 7.11; 95% CI, 3.87-13.08), bile duct exploration, postoperative chronic anemia, and postoperative pneumonia or urinary tract infection. Conclusions. Acute cholecystitis or obstruction was associated with significantly increased risk of SSI with laparoscopic but not open cholecystectomy. The risk of SSI was similar for planned open and converted procedures. These findings suggest that stratification by operative factors is important when comparing SSI rates between facilities. [ABSTRACT FROM AUTHOR]