Background: Observational studies have shown an increased risk of BC with use of HRT. However, data on the prognosis of BC that develop in HRT users are inconsistent. The association between HRT use and results of the 21-gene Recurrence Score (RS) assay (Oncotype DX, Genomic Health Inc.) has not been investigated. We aimed to analyze this association, and examine the actual rate of distant recurrence or death in this population. Methods: Clalit Health Services (CHS) is the largest health maintenance organization (HMO) in Israel. We identified all CHS newly diagnosed ER+, N- breast-cancer patients, aged 45-60 that performed a RS assay between 01/2006-12/2012 and that were treated for at least three months with HRT during the eight years before BC diagnosis. A 1:4 matched-cohort analysis was performed, with matching made according to age and year of BC diagnosis. Clinical and demographic data were extracted from the CHS centralized registry for all patients. RS assay scores was grouped according to the TAILORX categorization and distribution was compared using Chi-square test. Kaplan-Meier analysis with log-rank test was performed in order to compare time to a combined outcome of distant-recurrence and mortality. Results: A cohort of 259 HRT-treated patients was identified and matched with 1001 controls, not treated with HRT. The proportions of low-risk patients (RS 0-25) and high-risk patients (RS 26-100) were 76.8% and 23.2%, respectively, within HRT-treated patients, and 80.4% and 19.6% within controls. Chi square test was not found significant (χ²= 1.634, p = 0.201). The mean follow-up time was 148.4 months for the cases and 146.9 months for controls, with log-rank test not showing a significant difference between groups. Conclusions: These data did not show significant association between HRT use and higher RS assay scores, and also did not find an association between HRT use and actual distant recurrence or death. Although the proportion of patients with high risk RS appeared to be slightly higher within HRT treated patients, this difference had not reached significance and further studies are required.