OBJECTIVES: National guidelines recommend a 21-gene Recurrence Score (RS) to aid in adjuvant treatment decision in estrogen-receptor-positive, node-negative early stage breast cancer (ER+, LN- ESBC) patients. To assess the economic implication of the assay in community practices from the perspective of an US payer. METHODS: Analysis of 952 women with ESBC enrolled with Humana, Inc. (Louisville, KY) tested with the 21-gene RS between June, 2006 and June, 2010.  The proportion of women classified by the assay by RS risk categories, utilization and costs of chemotherapy regimens, and supportive care, and costs of adverse events were obtained from Humana. We adapted a validated Markov model to compute the cost implications of RS for a representative patient. The probability of risk of recurrence, chemotherapy benefits and decision impact of RS were derived from published studies. RESULTS: 255 patients within the tested population received adjuvant chemotherapy. Adjuvant chemotherapy was administered to 10% of women at low risk, 36% of women at intermediate risk, and 72% of women at high risk of recurrence.  Based on a meta-analysis in the reduction of chemotherapy after RS, the model estimated an average per patient test saving of $1,115. The immediate direct savings for chemotherapy drug, supportive care, and management of adverse events were $1,897, $2,593, $475, respectively. Prevention of recurrence through appropriate treatment of high-risk patients resulted in additional saving of $126. CONCLUSIONS: The adoption of the 21-gene RS lead to targeted management of women with ER+, LN- ESBC, and consequently save direct medical costs.