The purpose of this study is to evaluate the relationship between TOP2A RNA expression and recurrence in patients with operable estrogen receptor (ER)-positive breast cancer. We evaluated TOP2A expression in a pooled analysis of four independent datasets with gene expression data including 752 patients with early stage, ER-positive, HER2-negative breast cancer, most of whom received either no adjuvant therapy or only endocrine therapy without chemotherapy. We also used an algorithm to simulate the Oncotype DX Recurrence Score (simRS) and the proliferation component of the Recurrence Score (simPS). Results are expressed as the hazard ratio (HR) for estimates of the effect of a 1SD increase in the value of the log gene expression (x + 1SD vs. x) as a continuous function. TOP2A expression was significantly associated with recurrence (HR 1.56, p < 0.0001), and after adjustment for simRS (HR 1.26, p = 0.003). TOP2A correlated somewhat with simRS (0.45), but more strongly with simPS (0.69). For those with an intermediate simRS, high TOP2A expression (above the median) was associated with significantly higher relapse rates at 5 years (HR 1.82, p = 0.007). TOP2A expression provides prognostic information in patients with ER-positive, HER2-negative breast cancer, a population known to have low incidence of TOP2A gene alterations. These findings confirm prior reports indicating that TOP2A expression provides prognostic information in ER-positive breast cancer. TOP2A expression may also be useful for identifying those with an intermediate RS who are more likely to relapse, although additional validation in datasets including measured rather than simulated RS will be required.