Abstract Background Neoadjuvant therapy is considered for patients with hormone receptor (HR) positive/Human Epidermal Growth factor Receptor (HER) 2 negative breast cancers primarily to reduce tumor size and optimize surgical outcomes, and improve the chances for breast conservation. This approach rarely leads to pathological complete response and raises concerns about potential adverse outcomes due to delaying surgery. The objective of this study was to compare long term outcomes in patients receiving neoadjuvant (NAC) versus adjuvant chemotherapy (AC) for node positive breast cancer and to analyze survival in these groups when stratified by clinical stage. Methods We sampled the National Cancer Database (NCDB) (2004-2016) for patients with HR positive [estrogen receptor (ER) positive and/or progesterone receptor (PR) positive], HER2 negative, clinically diagnosed node positive breast cancers. We performed a multivariate logistic regression analysis to summarize demographic, geographic, and disease characteristics associated with the specific chemotherapy regimen. We then used multivariate cox regression models to compare hazard ratios for the same variables and plotted Kaplan-Meier survival plots to look for survival rate differences (S) between NAC and AC stratified by stage IIA, IIB, IIIA, and IIIB. Results Out of the 134,704 female patients who were included in this analysis (79.2% Caucasian, mean age 59.13 years), 24.9% received NAC, and 46.3% AC. In our study, patients older than 70 years had lower odds of receiving either NAC or AC (NAC: OR = 0.33, 95% CI = 0.31 - 0.35, p <0.001 and AC: OR = 0.31, 95% CI = 0.29 - 0.32, p < 0.0001) while those on private insurance had increased odds of getting either NAC or AC (NAC: 1.33, 95% CI = 1.23 - 1.45, p < 0.001 and AC: OR = 1.13, 95% CI = 1.06 - 1.21, p = <0.001) as compared to their counterparts. Patients with higher income (OR = 1.134, 95% CI = 1.064 - 1.209, p = <0.001), and those receiving treatment at an Integrated Network Cancer Program (OR = 1.405, 95% CI = 1.318 - 1.498, p < 0.001) were associated with higher odds of receiving NAC as compared to AC. However, patients were less to receive AC at an Integrated Network Cancer Program (OR = 0.784, 95% CI = 0.743 - 0.828, p <0.001), and with a Charlson/Deyo score of 3 or more (OR = 0.632, 95% CI = 0.561 - 0.712, p <0.001). Upon stratification, NAC as opposed to AC was associated with a longer S for patients with Stage IIIB (NAC: median S = 108.19 months, 95% CI = 101.71 - 114.67, and AC: median S = 89.63, 95% CI = 82.78 - 96.48, p <0.001). While data for stage IIA showed similar survival rates for both NAC and AC, it favored AC for other stages (IIB and IIIA). We analyzed characteristics associated with the benefit from chemotherapy overall, and noted that in patients with HR+, HER2 negative and node positive breast cancer, patients who received chemotherapy had a predicted greater survival as opposed to those who did not receive any chemotherapy whether NAC (HR = 0.565, 95% CI = 0.545 - 0.586, p < 0.001) or AC (HR = 0.545, 95% CI = 0.529 - 0.561, p < 0.0001). Hispanic ethnicity ( HR = 0.721, 95% CI = 0.661 - 0.787, p <0.001), private insurance (HR = 0.510, 95% CI = 0.479 - 0.544, p < 0.001), higher income (HR = 0.869, 95% CI = 0.826 - 0.914, p <0.001), care at an academic program (HR = 0.870, 95% CI = 0.833 - 0.908, p <0.001) and being located in the West South Central region (HR = 0.860, 95% CI = 0.803 - 0.921, p <0.001) were associated with greater S as compared to their counterparts in their respective subgroups. Conclusions In this large database, our data suggests that AC confers superior survival, compared to NAC in patients with HR positive, HER2 negative, and node positive breast cancer except for patients with Stage IIIB breast cancer. Also, chemotherapy given in any setting appears to improve survival overall. Citation Format: Iktej Singh Jabbal, Diana Saravia, Marita Yaghi, Nadeem Bilani, Leah Elson, Hong Liang, Zeina Nahleh. Comparative outcomes of Neoadjuvant versus Adjuvant chemotherapy in HR+/HER2- node positive breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-12-17.