To assess the patterns and predictors of locoregional recurrence (LRR) and distant failure (DF) after neoadjuvant chemotherapy among patients treated with mastectomy vs. breast-conserving surgery (BCS). Our secondary objective is to identify the predictors of failure among patients who achieved complete pathological response (pCR). Between 2000 and 2021, 1111 patients who had unilateral breast cancer were identified retrospectively in a single-institution database of consecutive patients who were treated with mastectomy or BCS following neoadjuvant chemotherapy. Multivariable analysis was performed using Cox proportional hazards model to identify the independent predictors associated with LRR and DF. Subgroup analysis was performed to identify the predictive factors associated with LRR and DF among patients (n = 273) who achieved pCR. The median follow-up for the entire cohort was 5.9 years (range, 1.2 months - 21.8 years). For LRR, the 10-year cumulative incidence was 12.9% and 5.8% in BCS and mastectomy cohorts, respectively (HR 1.7, p = 0.03). For DF, the 10-year cumulative incidence was 19.9% and 29.4% in BCS and mastectomy cohorts, respectively (HR 0.65, p = 0.005). In mastectomy patients, the following factors were associated with LRR: lymphovascular invasion (LVI) (HR 3.8, p< 0.001) and luminal A or B subtype (HR 0.32, p = 0.002), while in BCS patients, LVI (HR 2.3, p = 0.039), extracapsular extension (ECE) (HR 4.5, p< 0.001), and luminal A or B subtype (HR 0.24, p< 0.001) were associated with LRR. Regarding risk factors for DF: LVI (HR 1.97, p< 0.001), number of malignant lymph nodes (HR 1.06, p< 0.001), achieving pCR (HR 0.26, p = 0.001), and triple-negative disease (HR 1.8, p = 0.005) were identified in mastectomy patients, while LVI (HR 2.64, p = 0.002), number of malignant lymph nodes (HR 1.13, p< 0.001), ECE (HR 2.07, p = 0.03), and triple-negative disease (HR 2.9, p = 0.001) were associated with DF for BCS patients. Subgroup analysis for those who achieved pCR showed that cN0 stage (HR 0.16, p = 0.08) and undergoing mastectomy (HR 0.4, p = 0.07) were associated with a lower risk of recurrence, whether LRR or DF, in those patients. Our study demonstrates that LVI, biological subtype, ECE, tumor response, and the number of malignant lymph nodes after neoadjuvant chemotherapy are significant independent predictors of LRR and/or DF. These findings highlight the therapeutic significance of incorporating further therapy to optimize outcomes in these patients. In addition, patients with clinical node-negative at initial presentation and those undergoing mastectomy are associated with a low risk of subsequent failure after achieving pCR. This hypothesis-generating data highlights the role of revisiting the surgical approach for patients achieving pCR after neoadjuvant chemotherapy.