Background <p>Prior&#xa0;studies comparing different imaging modalities in assessing axillary response&#xa0;after neoadjuvant systemic therapy (NST) in locally advanced breast cancer (LABC) are limited. This study evaluated the efficacy of different imaging modalities in identifying residual lymphadenopathy after NST in modern cohort of LABC patients.</p> Methods <p>A retrospective review was performed examining LABC patients undergoing NST followed by surgical axillary staging from 2018 to 2023. Patients with LABC (T3-4,N1-3 or any T stage with N2-3 disease) were included. Inflammatory breast cancer&#xa0;was excluded. The efficacy of US, MRI, and PET/CT in evaluating residual nodal disease and the variables associated with radiologic-pathologic concordance were analyzed.</p> Results <p>A total of 101 patients meeting inclusion were identified. Post-NST imaging included US (<i>n</i> = 57), MRI (<i>n</i> = 53), and PET/CT (<i>n</i> = 45). Ultrasound had the highest sensitivity of 71% and positive predictive value of 76%. PET/CT had the highest specificity of 73% and negative predictive value of 70%. MRI had the lowest performance in all diagnostic measures.</p> <p>There was a significant relationship between complete imaging response (CIR)-pathologic complete response (pCR) concordance and pretreatment nodal status (<i>χ</i>²(57) 8.9,&#xa0;<i>p</i> = 0.01). Higher <i>N</i> stage&#xa0;was associated with CIR-pCR concordance with cN3 disease having the highest odds compared with cN1 disease (OR 6.2,&#xa0;<i>p</i> = 0.006). The absence of lymphovascular invasion was associated with CIR-pCR concordance (OR 9.2,&#xa0;<i>p</i> = 0.008).</p> Conclusions <p>Post-NST imaging provides valuable information on treatment response in LABC. However, CIR should not preclude surgical axillary evaluation. Further studies investigating the relationships between pre-treatment nodal status in LABC patients and radiologic-pathologic complete response after NST are warranted.</p>