OBJECTIVE Survey results suggest that prolonged administration of prophylactic antibiotics is common after mastectomy with reconstruction. We determined utilization, predictors, and outcomes of postdischarge prophylactic antibiotics after mastectomy with or without immediate breast reconstruction. DESIGN Retrospective cohort. PATIENTS Commercially insured women aged 18-64 years coded for mastectomy from January 2004 to December 2011 were included in the study. Women with a preexisting wound complication or septicemia were excluded. METHODS Predictors of prophylactic antibiotics within 5 days after discharge were identified in women with 1 year of prior insurance enrollment; relative risks (RR) were calculated using generalized estimating equations. RESULTS Overall, 12,501 mastectomy procedures were identified; immediate reconstruction was performed in 7,912 of these procedures (63.3%). Postdischarge prophylactic antibiotics were used in 4,439 procedures (56.1%) with immediate reconstruction and 1,053 procedures (22.9%) without immediate reconstruction (P<.001). The antibiotics most commonly prescribed were cephalosporins (75.1%) and fluoroquinolones (11.1%). Independent predictors of postdischarge antibiotics were implant reconstruction (RR, 2.41; 95% confidence interval [CI], 2.23-2.60), autologous reconstruction (RR, 2.17; 95% CI, 1.93-2.45), autologous reconstruction plus implant (RR, 2.11; 95% CI, 1.92-2.31), hypertension (RR, 1.05; 95% CI, 1.00-1.10), tobacco use (RR, 1.07; 95% CI, 1.01-1.14), surgery at an academic hospital (RR, 1.14; 95% CI, 1.07-1.21), and receipt of home health care (RR, 1.11; 95% CI, 1.04-1.18). Postdischarge prophylactic antibiotics were not associated with SSI after mastectomy with or without immediate reconstruction (both P>.05). CONCLUSIONS Prophylactic postdischarge antibiotics are commonly prescribed after mastectomy; immediate reconstruction is the strongest predictor. Stewardship efforts in this population to limit continuation of prophylactic antibiotics after discharge are needed to limit antimicrobial resistance. Infect Control Hosp Epidemiol 2017;38:1048-1054.