Abstract Background Tumor genomic expression profile data are used to guide chemotherapy choice, but there are gaps in evidence for women aged 65 years and older. We estimate chemotherapy effects by age and comorbidity level among women with early-stage, hormone receptor–positive, human epidermal growth factor receptor 2 (HER2)–negative breast cancers and Oncotype DX scores of 26 or higher. Methods A discrete-time stochastic state transition simulation model synthesized data from population studies and clinical trials to estimate outcomes over a 25-year horizon for subgroups based on age (65–69, 70–74, 75–79, and 80–89 years) and comorbidity levels (no or low, moderate, severe). Outcomes were discounted at 3%, and included quality-adjusted life-years (QALYs), life-years, and breast cancer and other-cause mortality with chemoendocrine vs endocrine therapy. Sensitivity analysis tested the effect of varying uncertain parameters. Results Women aged 65–69 years with no or low comorbidity gained 0.16 QALYs with chemo-endocrine and reduced breast cancer mortality from 34.8% to 29.7%, for an absolute difference of 5.1%; this benefit was associated with a 12.8% rate of grade 3–4 toxicity. Women aged 65–69 years with no or low or moderate comorbidity levels, and women aged 70–74 years with no or low comorbidity had small chemotherapy benefits. All women aged 75 years and older experienced net losses in QALYs with chemo-endocrine therapy. The results were robust in sensitivity analyses. Chemotherapy had greater benefits as treatment effectiveness increased, but toxicity reduced the QALYs gained. Conclusion Among women aged 65–89 years whose tumors indicate a high recurrence risk, only those aged 65–74 years with no or low or moderate comorbidity have small benefits from adding chemotherapy to endocrine therapy. Genomic expression profile testing (and chemotherapy use) should be reserved for women aged younger than 75 years without severe comorbidity.