Abstract Background The benefits of chemotherapy in node-negative, hormone receptor-positive, and human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients with the 21-gene recurrence score (RS) of 18–30, particularly those with RS 26–30, are not known. Methods Using the Surveillance, Epidemiology, and End Results (SEER) data, we retrospectively identified 29,137 breast cancer patients with the 21-gene RS of 18–30 diagnosed between 2004 and 2015. Mortality risks according to the RS and chemotherapy use were compared by the Kaplan-Meier method and Cox’s proportional hazards model. Results Among the breast cancer patients with the RS 18–30, 21% of them had RS 26–30. Compared to breast cancer patients with RS 18–25, patients with RS 26–30 had more aggressive tumor characteristics and chemotherapy use and increased risk of breast cancer-specific mortality and overall mortality. In breast cancer patients who were aged ≤ 70 years and had RS of 26–30, chemotherapy administration was associated with a 32% lower risk of breast cancer-specific mortality (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.47–0.99) and a 42% lower risk of overall mortality (HR, 0.58; 95% CI, 0.44–0.76). Survival benefits were most pronounced in breast cancer patients who were younger or had grade III tumor. Conclusions The 21-gene RS of 18–30 showed heterogeneous outcomes, and the RS 26–30 was a significant prognostic factor for an increased risk of mortality. Adjuvant chemotherapy could improve the survival of node-negative, hormone receptor-positive, and HER2-negative breast cancer patients with the 21-gene RS 26–30 and should be considered for patients, especially younger patients or patients with high-grade tumors.