Background: Understanding surgical site infection (SSI) risk factors after breast operation is essential to develop infection-prevention strategies and improve surgical outcomes. Methods: We performed a retrospective case-control study with subjects selected from a cohort of mastectomy, breast reconstruction, and reduction surgical patients between January 1998 and June 2002 at a university-affiliated hospital. SSI cases within 1 year after operation were identified using ICD-9-CM diagnosis codes for wound infection and complication or positive wound cultures, or both. Medical records of 57 patients with breast SSI and 268 randomly selected uninfected control patients were reviewed. Multivariate logistic regression was used to identify independent risk factors for SSI. Results: Significant independent risk factors for breast incisional SSI included insertion of a breast implant or tissue expander (odds ratio [OR] = 5.3; 95% CI, 2.5 to 11.1), suboptimal prophylactic antibiotic dosing (OR = 5.1; 95% CI, 2.5 to 10.2), transfusion (OR = 3.4; 95% CI, 1.3 to 9.0), mastectomy (OR = 3.3; 95% CI, 1.4 to 7.7), previous chest irradiation (OR = 2.8; 95% CI, 1.2 to 6.5), and current or recent smoking (OR = 2.1; 95% CI, 0.9 to 4.9). Local infiltration of an anesthetic agent was associated with substantially reduced odds of SSI (OR = 0.4; 95% CI, 0.1 to 0.9). Conclusions: Suboptimal prophylactic antibiotic dosing is a potentially modifiable risk factor for SSI after breast operation. SSI risk was increased in patients undergoing mastectomy and in patients who had an implant or tissue expander placed during operation. This information can be used to develop a specific risk stratification index to predict SSI and infection-preventive strategies tailored for breast surgery patients.