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Timing of prophylactic antibiotic administration for surgical procedures is a nationally mandated and publicly reported quality metric sponsored by the Centers for Medicare and Medicaid Services Surgical Care Improvement Project. Numerous studies have failed to demonstrate that adherence to the Surgical Care Improvement Project prophylactic antibiotic timely administration measure is associated with decreased surgical site infection (SSI).To determine whether prophylactic antibiotic timing is associated with SSI occurrence.Retrospective cohort study using national Veterans Affairs patient-level data on prophylactic antibiotic timing for orthopedic, colorectal, vascular, and gynecologic procedures from 2005 through 2009.National Veterans Affairs Surgical Care Improvement Project data from 112 Veterans Affairs hospitals and matched Veterans Affairs Surgical Quality Improvement Program data.Patients undergoing hip or knee arthroplasty, colorectal surgical procedures, arterial vascular surgical procedures, and hysterectomy.Timing of prophylactic antibiotic administration with respect to surgical incision time.Data for prophylactic antibiotic agent, prophylactic antibiotic timing with respect to surgical incision, and patient and procedure risk variables were assessed for their relationship with the occurrence of a composite superficial or deep incisional SSI within 30 days after the procedure. Nonlinear generalized additive models were used to examine the association between antibiotic timing and SSI.Of the 32 459 operations, prophylactic antibiotics were administered at a median of 28 minutes (interquartile range, 17-39 minutes) prior to surgical incision, and 1497 cases (4.6%) developed an SSI. Compared with procedures with antibiotic administration within 60 minutes prior to incision, higher SSI rates were observed for timing more than 60 minutes prior to incision (unadjusted odds ratio [OR] = 1.34; 95% CI, 1.08-1.66) but not after incision (unadjusted OR = 1.26; 95% CI, 0.92-1.72). In unadjusted generalized additive models, we observed a significant nonlinear relationship between prophylactic antibiotic timing and SSI when considering timing as a continuous variable (P = .01). In generalized additive models adjusted for patient, procedure, and antibiotic variables, no significant association between prophylactic antibiotic timing and SSI was observed. Vancomycin hydrochloride was associated with higher SSI occurrence for orthopedic procedures (adjusted OR = 1.75; 95% CI, 1.16-2.65). Cefazolin sodium and quinolone in combination with an anaerobic agent were associated with fewer SSI events (cefazolin: adjusted OR = 0.49; 95% CI, 0.34-0.71; quinolone: adjusted OR = 0.55; 95% CI, 0.35-0.87) for colorectal procedures.The SSI risk varies by patient and procedure factors as well as antibiotic properties but is not significantly associated with prophylactic antibiotic timing. While adherence to the timely prophylactic antibiotic measure is not bad care, there is little evidence to suggest that it is better care.