Background TAILORx demonstrated that women with node-negative, hormone receptor-positive, HER2-negative breast cancers and Oncotype DX recurrence scores (RS) of 0–25 had similar 9-year outcomes with endocrine vs chemo-endocrine therapy; evidence for women aged 50 years and younger and RS 16–25 was less clear. We estimated how expected changes in practice following the trial might affect US costs in the initial 12 months of care (initial costs). Methods Data from Surveillance, Epidemiology, and End Results (SEER), SEER-Medicare, and SEER-Genomic Health Inc datasets were used to estimate Oncotype DX testing and chemotherapy rates and mean initial costs pre- and post-TAILORx (in 2018 dollars), assuming all women received Oncotype DX testing and score-suggested therapy posttrial. Sensitivity analyses tested the impact on costs of assumptions about compliance with testing and score-suggested treatment and estimation methods. Results Pretrial mean initial costs were $2.816 billion. Posttrial, Oncotype DX testing costs were projected to increase from $115 to $231 million and chemotherapy use to decrease from 25% to 17%, resulting in initial care costs of $2.766 billion, or a net savings of $49 million (1.8% decrease). A small net savings was seen under most assumptions. The one exception was if all women aged 50 years and younger with tumors with RS 16–25 elected to receive chemotherapy, initial care costs could increase by $105 million (4% increase). Conclusions Personalizing breast cancer treatment based on tumor genetic profiles could result in small cost decreases in the initial 12 months of care. Studies are needed to evaluate the long-term costs and nonmonetary benefits of personalized cancer care.