Purpose: The use of neoadjuvant chemotherapy (NAC) in patients with operable breast cancer allows for assessment of treat-ment response and subsequent tailoring of adjuvant therapy. Data are limited with respect to outcomes among patients with a heavy residual tumor burden after NAC. We report outcomes in patients who had exceptionally poor responses to NAC: those with >9 involved nodes after NAC or with 5 cm or more of residual disease in the breast.Methods and Materials: Between June 2014 and April 2020, 1511 patients with breast cancer received NAC followed by sur-gery at our institution. Poor responders, defined as those with positive nodes or residual tumor in the breast, were identified for analysis. Patients were further classified into 3 groups for comparison purposes: (1) 1 to 3 positive nodes; (2) 4 to 9 positive nodes; or (3) >9 positive nodes and/or >5 cm of residual tumor, which was defined as high-volume residual (HVR). Recur-rence and survival outcomes were compared based on residual disease burden after NAC.Results: Among 934 poor responders, 539 patients had 1 to 3 positive nodes (ypN1), 215 had 4 to 9 positive nodes (ypN2), and 180 had HVR disease. Specifically, 118 had >9 positive nodes (HVR), and 62 patients had >5 cm of residual tumor in the breast. With a median follow-up of 31 months (interquartile range, 18-46), the 5-year overall survival rate was 88% among ypN1, 76% among ypN2, and 72% among patients with HVR disease (P < .001). The 5-year distant recurrence-free survival and locoregional recurrence incidences were 82% and 7.6% among ypN1 versus 67% and 8.4% among ypN2 versus 53% and 12% among HVR, respectively.Conclusions: Our work suggests that patients with HVR disease are at high risk for locoregional and distant recurrence as well as death, despite best available standard-of-care treatment. Intensification of locoregional therapies and/or alternative adjuvant systemic treatment may improve outcomes in these poor responders.(c) 2022 Elsevier Inc. All rights reserved.