Background: A greater proportion of patients with surgical risk factors are undergoing immediate breast reconstruction after mastectomy, resulting in the need for better risk prediction to inform decisions about the procedure. The objective of this study was to leverage clinical data to restructure a previously developed risk model to predict serious infectious and noninfectious wound complications after mastectomy alone and mastectomy plus immediate reconstruction for use during a surgical consultation. Methods: The study established a cohort of women age 21 years or older treated with mastectomy from 1 July 2010 to 31 December 2015 using electronic health records from two hospitals. Serious infectious and non-infectious wound complications, defined as surgical-site infection, dehiscence, tissue necrosis, fat necrosis requiring hospitalization, or surgical treatment, were identified within 180 days after surgery. Risk factors for serious wound complications were determined using modified Poisson regression, with discrimination and calibration measures. Bootstrap validation was performed to correct for overfitting. Results: Among 2159 mastectomy procedures, 1410 (65.3%) included immediate implant or flap reconstruction. Serious wound complications were identified after 237 (16.8%) mastectomy-plus-reconstruction and 30 (4.0%) mastectomy-only procedures. Independent risk factors for serious wound complications included immediate reconstruction, bilateral mastectomy, higher body mass index, depression, and smoking. The optimism-corrected C statistic of the risk prediction model was 0.735. Conclusions: Immediate reconstruction, bilateral mastectomy, obesity, depression, and smoking were significant risk factors for serious wound complications in this population of women undergoing mastectomy. Our risk prediction model can be used to counsel women before surgery concerning their individual risk of serious wound complications after mastectomy.