Background: Evidence is scarce about the influence of comorbidity on short-term outcomes of patients with breast cancer after surgery. The objective of this study was to examine the effect of comorbidity on risk of postoperative complications, prolonged hospitalization (defined as above median length of stay), and in-patient death among women with breast cancer. Methods: National inpatient sample is a nationwide clinical and administrative database. Patient discharges with primary diagnosis code of breast cancer and coincident procedure code for breast surgery from 2005 to 2009 were identified using International Disease Codes 9th edition (ICD-9). Information about demographics, hospital characteristics, comorbidities, stage, surgical treatment, postoperative complications, length of hospital stay, and in-patient deaths was obtained. Comorbidities were identified using ICD-9 codes and used to calculate modified Charlson comorbidity index (CCI) score. We divided patients based on these scores into 4 groups: 0, 1, 2, and 3 or more. Multivariate logistic regression analyses were used to examine risk adjusted association between CCI score and the aforementioned outcomes. Results: We identified 75,100 patient discharges with a mean age of 61 years. Compared to patients with a CCI score of 0, as a reference group, CCI scores of 1, 2, and 3 or more increased the risk of post-operative complications by 1.7 fold, 2.6 fold, and 4.6 fold, respectively (p <0.001). Compared to patients with a CCI score of 0, CCI scores of 1, 2, and 3 or more increased the risk of prolonged hospitalization by 1.2 fold, 1.6 fold, and 2.3 fold, respectively (p <0.001). Similarly, Compared to patients with a CCI score of 0, CCI scores of 1, 2, and 3 or more increased the risk of in-patient death by 3.1 fold, 5.4 fold, and 15.8 fold, respectively (p <0.001). Conclusions: After controlling for potential confounders, we found a strong and statistically significant association between comorbidity and outcomes of patients with breast cancer after surgery. Effective control of comorbidity in breast cancer patients may reduce post-operative morbidity and mortality.