558 Background: The development of novel anti-HER2 drugs opens new treatment options, including women with lower expression of HER2. This study aimed to compare local/regional HER2-low and HER2-0 breast cancer outcomes in the real world. Methods: Women diagnosed between 2010 and 2017 with clinical stage I-III breast cancers with low HER2 expression or HER2-zero (0) expression were identified in the National Cancer Database (NCDB), a nationwide oncology outcomes database in the United States. HER2-Low was defined as IHC1+ or 2+/ISH negative, whereas HER2-zero was IHC-0. The primary outcome was overall survival (OS). We performed a multivariable Cox regression model to estimate hazard ratios and adjusted for the following factors: age, race/ethnicity, education, insurance, comorbidities, grade, stage, lymph nodes, type of surgery, the type of cancer center, and if any chemotherapy, any hormonal therapy, and any adjuvant radiation in the first treatment course. Stratification factors were hormone receptor status. Subgroup analyses for those who received neoadjuvant (NAC), adjuvant (AC), and no chemotherapy were performed, and the pathologic complete response (pCR) rates in NAC groups were estimated. Results: 376,199 (68%) women with HER2-low tumors and 177,298 (32%) with HER2-0 tumors were analyzed. 336,147 (89%) of the HER2-low tumors and 141,528 (79%) of the HER2-0 tumors were HR-positive. Low HER2 expression was associated with longer OS in both HR-positive (adjusted Hazard Ratio (aHR): 0.94, 95%CI 0.93-0.96, p<0.001) and HR-negative diseases (aHR: 0.88, 95%CI 0.85-0.91, p<0.001). HR-positive, HER2-low tumors had statistically significantly better survival than HR-positive, HER2-0 tumors in NAC (aHR 0.84, 95%CI 0.79-0.90, p<0.001) and AC (aHR 0.90, 95%CI 0.85-0.94, p<0.001) groups, but not in the no-chemo group (aHR 1.02, 95%CI 1.00-1.05, p=0.09, p interaction<0.001). In contrast, HR negative, HER2-low tumors had better OS than HR negative, HER2-0 tumors in all subgroups, regardless of receipt or timing of chemotherapy (NAC aHR 0.88, 95%CI 0.83-0.94, p<0.001, AC aHR 0.86, 95%CI 0.81-0.92, p<0.001, No chemo aHR 0.93, 95%CI 0.87-0.99, p=0.03, p interaction=0.06). In NAC groups, HER2-low expression was linked to lower pCR rates in both HR-positive (8.9% vs. 11.2%, p<0.001) and HR-negative (31.2% vs. 34.1%, p<0.001). Conclusions: Local/regional HER2-low breast cancer has better survival than HER2-0 breast cancer, irrespective of its hormone receptor status. The survival advantage was observed in HR-negative disease and only with receipt of chemotherapy in HR-positive breast cancer. Specific therapies, such as trastuzumab deruxtecan, have activity in HER2-low breast cancers, and other therapeutics for HER-2 low diseases should be sought.