Background: This study examined whether associations between 21-gene recurrence score (RS) genomic testing and lower costs among patients with early-stage, estrogen receptor–positive breast cancer are observable in real-world data from the Medicare population. Methods: A retrospective cohort study was conducted using SEER-Medicare data for a nationally representative sample of Medicare beneficiaries diagnosed from 2005 through 2011. The main outcomes were associations between RS testing and overall and chemotherapy-specific costs. The primary analysis was restricted to patients aged 66 to 75 years. Results: The primary analysis comprised 30,058 patients. Mean costs 1 year after diagnosis were $35,940 [SD, $28,894] overall, $51,127 [33,386] for clinically high-risk disease, $33,225 [$27,711] for intermediate-risk disease, and $26,695 [$19,532] for low-risk disease. Chemotherapy-specific costs followed similar trends. In multivariable analyses, RS testing was associated with significantly lower costs among high-risk patients in terms of both relative costs (cost ratio, 0.88; 99% CI, 0.82–0.94) and absolute costs ($6,606; 99% CI, $39,223–$9,290). Higher costs among low-risk and intermediate-risk patients were mainly caused by higher noncancer costs. In sensitivity analyses that included all patients aged ≥66 years (N=64,996), associations between RS testing and costs among high-risk patients were similar but less pronounced because of lower overall use of chemotherapy. Conclusions: RS testing was associated with lower overall and chemotherapy-related costs in patients with high-risk disease, consistent with lower chemotherapy use among these patients. Higher overall costs for patients with intermediate-risk and low-risk disease were driven largely by non–treatment-related costs.