Neoadjuvant chemotherapy (NAC) increases rates of successful breast conserving surgery (BCS) in patients with breast cancer. However, some studies suggest that BCS after NAC may confer increased risk of locoregional recurrence (LRR). We assessed LRR rates and locoregional recurrence free survival (LRFS) in patients enrolled on I-SPY2 (NCT01042379), a prospective NAC trial for patients with clinical stage II-III, molecularly high-risk breast cancer. Cox proportional hazards models were used to evaluate associations between surgical procedure (BCS vs. mastectomy) and LRFS adjusted for age, tumor receptor subtype, clinical T category, clinical nodal status, and Residual Cancer Burden (RCB). In 1,462 patients, surgical procedure was not associated with LRR or LRFS on either univariate or multivariate analyses. The unadjusted incidence of LRR was 5.4% after BCS, and 7.0% after mastectomy, at median follow up time of 3.5 years. The strongest predictor of LRR was RCB class, with each increasing RCB class having significantly higher hazard ratio for LRR compared to RCB 0 on multivariate analysis. Triple negative receptor subtype was also associated with increased risk of LRR (HR 2.91, 95% CI 1.8-4.6, P<0.0001), regardless of type of operation. In this large multi-institutional prospective trial of patients completing NAC, we found no increased risk of LRR or differences in LRFS following BCS compared to mastectomy. Tumor receptor subtype and extent of residual disease after NAC were significantly associated with recurrence. These data demonstrate that BCS can be an excellent surgical option after NAC for appropriately selected patients.Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.