Background <p>The 5-item modified Frailty Index (mFI-5) is a clinical tool to predict adverse outcomes in surgical patients by assessing five comorbidities: diabetes, hypertension, congestive heart failure, chronic obstructive pulmonary disease, and dependent functional status. It helps to evaluate postoperative complication risks, recovery time, and overall survival, particularly in frail patients undergoing oncological and gynecological surgeries.</p> Methods <p>This retrospective cohort study analyzed American College of Surgeons, National Surgical Quality Improvement Program data from adult female patients undergoing mastectomy procedures without reconstruction between 2017 and 2022. Patients were selected based on Current-Procedural-Terminology codes, excluding incomplete or non-breast-related cases. Preoperative, perioperative, and 30-day postoperative data were analyzed using logistic and linear regression models, with the mFI-5 cutoff set at 2.</p> Results <p>Between 2017 and 2022, 860 patients underwent mastectomies at Yale Healthcare Network; 19% (<i>n</i> = 163) had mFI score ≥2. High-risk patients (mFI ≥2) were significantly older (66.32 ± 10.83&#xa0;years) and had a higher body mass index (33.69 ± 7.73, both <i>p</i> &lt; 0.001). Surgical complications occurred in 11.98% of patients, with a higher rate in the high-risk group (22.7% vs. 9.5%, <i>p</i> &lt; 0.001). Adjusted multivariate logistic regression showed an increased risk of complications in frail patients (aOR 2.66; [1.60–4.43], <i>p</i> &lt; 0.001). Although slight reductions in hospital stay and surgery duration were observed for high-risk patients, these differences were not significant. Sensitivity analysis confirmed higher odds of complications, including acute kidney failure (odds ratio [OR] 9.01) and pneumonia (OR 4.10).</p> Conclusions <p>The mFI-5 is a robust tool for predicting surgical complications in patients undergoing mastectomy, particularly those with multiple comorbidities.</p>