Background: The nationwide use of the 21-gene recurrence score (21-RS) and implications regarding chemotherapy administration in relation to clinical risk in early breast cancer patients are investigated. Methods: Breast cancer patients surgically treated between 2014 and 2016 were selected from the Netherlands Cancer Registry and categorized as having a clinical low, intermediate, or high risk of developing metastases. Deployment of the 21-RS is advocated in patients with an intermediate risk of developing metastases. The use and impact of the 21-RS test result on chemotherapy administration were assessed in relation to the clinical risk as well as patient and tumor characteristics; χ 2 tests were used for analysis. Results: Of all patients, 20,488 were considered as clinical low-, 4,309 as intermediate-, and 15,266 as high-risk patients. The 21-RS was deployed in 0.1% ( n = 23), 3.2% ( n = 137), and 0.6% ( n = 90) of these categories, respectively. In the clinical intermediate-risk group, the 21-RS assigned 73.7, 13.1, and 13.1% of patients to the genomic low-, intermediate-, and high-risk category, respectively. Adherence to the 21-RS was 95.6% in these patients. Conclusion: In the Netherlands, the 21-RS test is applied both inside and outside the guideline-directed area. In case of discordance between the genomic and clinical risk, patients were treated in line with the result of the 21-RS.