Background There is an increase in the use of neoadjuvant chemotherapy (NACT) to downstage breast cancer. Sentinel lymph node biopsy (SLNB) has replaced Axillary lymph node dissection (ALND) as a standard of care for the treatment of breast cancer patients with negative axilla at presentation. However, the reliability of SLNB after NACT in patients with initially node-positive breast cancer is still controversial and debatable. This meta-analysis was conducted to investigate the accuracy and feasibility of SLNB after NACT in patients presented with positive axillary lymph nodes. Methods A comprehensive literature search was conducted using Medline, PubMed, Embase, Central, and SCOPUS for studies from their date of inception till April 2021 on the performance of SLNB following NACT in clinically node-positive breast cancer patients. We included prospective studies including breast cancer patients with positive lymph nodes at diagnosis, receiving neoadjuvant chemotherapy before undergoing an SLNB, irrespective of their molecular subtypes or breast cancer stage. We excluded retrospective studies, case reports, review articles, and letter to editors. The main outcomes of interest were the false negative rate (FNR) and the identification rate (IR). We also aimed to investigate the accuracy, negative predictive value (NPV), positive predictive value (PPV), specificity, and sensitivity of the SLNB procedure. Results An aggregate of 33 studies were included in this meta-analysis enrolling 4624 patients. The pooled identification rate (IR) was 88% (95% CI: 86-90; heterogeneity I2: 80.93 %) and the false negative rate (FNR) was 13% (95% CI: 11-15; heterogeneity I2: 72.31%). The pooled accuracy, NPV, PPV, specificity and sensitivity were 91.8% (95% CI: 69.39 -114.3), 82.8% (95%CI: 60.19-105.52), 98.2% (95%CI: 65.86 -130.63), 93.7% (95 CI%: 32.4 -155.03), 82.1% (95%CI: 58.38- 107.24) respectively. Conclusion In this comprehensive meta-analysis, we were able to review the largest number of studies (N=33) and patients (N=4624). We carried out this study with the intention to overcome the limitations of previously conducted meta-analyses such as including retrospective studies and a mixed population of clinically node-positive and node-negative breast cancer patients. Based on current findings, the usage of SLNB instead of ALND for the treatment of node-positive breast cancer patients is acceptable. However, further analysis is needed for the improvement of SLNB performance. Keywords: Sentinel lymph node biopsy; Breast cancer; Node positive; Neoadjuvant chemotherapy. Citation Format: Mariam Zahwe, Abir Ghzaiel, Malak Ghezzawi, Sarah El Iskandarani, Marwa Diab, Lara Soueid, Miryam El Jibbawi, Ahmad Najia, Khalil El Asmar, Eman Sbaity. Performance of Sentinel Lymph Node Biopsy after Neoadjuvant Chemotherapy in Clinically Node Positive Breast Cancer Patients: Systematic Review and Meta-analysis [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-25.