We report on a 56-year-old Caucasian female, diagnosed with locally advanced, hormone-receptor-positive, and human epidermal growth factor receptor 2 (HER2)-positive cancer of the left breast. The patient received neoadjuvant chemotherapy with adriamycin/cyclophosphamide (AC) followed by docetaxel/trastuzumab. A partial clinical and radiographical response was documented after four cycles of AC. Approximately one week after the first cycle of docetaxel and trastuzumab, the patient presented with diffuse edema, erythema, and induration involving the entire left breast. The differential diagnoses included infection, inflammatory response/reaction to docetaxel, or cancer progression. After a multidisciplinary review, the decision was made to stop the docetaxel and deliver neoadjuvant radiation treatment concurrent with trastuzumab. Approximately four weeks after radiation therapy completion, the patient underwent a left total mastectomy and axillary dissection, with pathologic complete response (pCR) in the breast and axillary nodal disease. After surgery, systemic therapy was resumed with paclitaxel and trastuzumab, with a plan to start adjuvant endocrine therapy after completion of chemotherapy. We will discuss clinical considerations in the management of the unexpected findings of acute inflammatory response in the breast and nodal regions during neoadjuvant chemotherapy. Associations between intrinsic breast cancer subtype and pCR in locally advanced breast cancer will also be reviewed.