Background: Early breast cancer is a heterogeneous disease, and, therefore, prognostic tools have been developed to evaluate the risk for distant recurrence. We compared the Clinical Treatment Score (CTS) with the Adjuvant Online Score (AOS) and the Risk for Recurrence Score (RRS) based on the expression of three proliferation markers (RACGAP1, Ki67 and TOP2A) in high-risk early breast cancer patients. Methods: A total of 1,681 patients, enrolled in two prospective phase III trials, were treated with anthracycline-based adjuvant chemotherapy. Formalin-fixed paraffin-embedded primary tumor tissue samples with adequate material were obtained from 898 patients. Sufficient RNA was extracted from 875 samples (52.1% of the randomized patients) followed by multiplex RT-PCR for assessing RACGAP1, Ki67, TOP2A and CALM2 mRNA expression. The CTS integrated the prognostic information from nodal status, tumor size, histological grade and age. Results: CTS was prognostic for disease-free survival (DFS, p<0.0001), while CTS, AOS and RRS were all prognostic for overall survival (OS, p<0.0001, p<0.0001, p=0.036, respectively). The use of AOS in addition to CTS added prognostic information regarding DFS (LR-Δχ² 11.9592, p<0.0001). However, the use of RRS in addition to CTS was not proven to be a better prognostic tool in terms of DFS (LR-Δχ² 0.8495; p=0.357). For estimating OS, the use of either AOS or RRS in addition to CTS added significant prognostic information. Specifically, the use of both CTS and AOS had significantly better prognostic value vs CTS alone (LR-Δχ² 28.2266, p<0.0001), as well as the use of CTS and RRS vs CTS alone (LR-Δχ²4.2057; p=0.040). Additionally, more patients were scored as high-risk by AOS than CTS. Conclusions: Using CTS, AOS or RRS provides prognostic information in high-risk early breast cancer patients, with more patients determined as high-risk by AOS. The combination of CTS and AOS adds significant prognostic information compared to CTS alone for DFS, while the combination of CTS with either AOS or RRS are better prognostic tools than CTS alone for OS.