Background: HER2-positivity is an essential marker for therapeutic decisions, while HER2 expression is heterogenous. In recent years, there has been increasing recognition of a subgroup of breast cancer patients who have low levels of HER2 expression, also known as HER2-low because trastuzumab deruxtecan offers clinical benefit for patients with HER2-low metastatic breast cancer. Despite the growing interest in HER2-low breast cancer, there is limited research on how multigene assays can help differentiate between HER2-low and HER2-negative breast cancer. Among ER+HER2- breast cancer, we compared genomic characteristics between HER2-low and HER2-zero using the 21-gene assay. Methods: A retrospective review of clinical records was performed in 2,295 patients who underwent Oncotype DX test in two hospitals between 2013 and 2020. Patients were classified into two groups as the HER2-zero and HER2-low based on HER2 IHC and SISH test. In cases with HER2 2+, no amplification of HER2 gene was confirmed by silver in situ hybridization. High genomic risk was defined as cases with 21-gene recurrence score (RS)>25. Multivariable binary logistic-regression analysis was performed. Results: Of these, 944 (41.1%) were assigned in the HER2-zero, and 1351 (58.9%) were in the HER2-low. The averages of RS were 17.082 in the HER2-zero breast cancer and 18.503 in the HER2-low, respectively (P-value<0.005). HER2 score identified by qRT-PCR was 8.912 in the HER2 zero group and was 9.337 in the HER2 low group (P<0.005). When we compared a proportion of high RS between two groups, the high RS rate was 12.4% (117 of 944) in the HER2-zero, while it was 17.0% (230 of 1351) in the HER2-low (p=0.002). In multivariable analysis, HER2-low was demonstrated as an independent factor for high RS with an odds ratio 1.517 (1.172-1.964) independent of ER, PR, and Ki67. Within the subgroup with invasive ductal carcinoma, the high RS rates of HER2-low and HER2-zero were 19% and 14%, respectively. In the all patients, recurrence-free survival and overall survival did not differ between HER2-low and HER2-zero groups. Conclusions: Within ER+HER2- breast cancer, HER2-low tumors are associated with high RS, especially for histologically invasive ductal carcinoma. A prognostic influence of HER2-low expression among ER+HER2- breast cancer remains as an area that requires further study.