Background: Current ASCO Antiemesis Guidelines recommend triple antiemetic therapy (a 5HT₃RA, an NK1, and dexamethasone) to prevent chemotherapy (CT) induced nausea and vomiting (CINV) in patients undergoing highly emetogenic chemotherapy (HEC). This study evaluated whether this regimen resulted in reduced rates of CINV in patients diagnosed with breast cancer (BC) and initiated on HEC. The primary outcomes of interest were rates of acute and delayed CINV in patients whose antiemesis prophylaxis was or was not in accordance with the ASCO guideline (i.e., Per-guideline vs. Non-Guideline). Costs of treating CINV were also calculated. Methods: Patients were identified in the Premier Healthcare database, a complete geographically diverse census of inpatients and hospital-based outpatients. Adults treated for BC with HEC during the years 2012-14 were identified and stratified based on their antiemesis prophylaxis. Rates of acute (day of CT) and delayed CINV (days 2-7 post CT) were calculated following initiation of HEC. CINV was defined by ICD9 codes for nausea and vomiting or volume depletion/dehydration or use of a rescue antiemetic. Rates of CINV and health care costs were then compared between the two cohorts. Results: A total of 8,388 patients were included in the analysis. Of these, 5,447 (65%) had treatment Per-Guideline and 2,941 (35%) were Non-Guideline. For acute CINV, Per-Guideline patients had a significantly lower rate of CINV when compared to Non-Guideline patients (1.7% vs. 3.2%, respectively, p < .001). Similarly, in delayed CINV Per-Guideline patients had significantly lower rates of CINV when compared to Non-Guideline patients (15.4% vs. 19.1%, p < .001). Patients who experienced CINV also had significantly greater total health care costs versus those without CINV ($32,199 vs. $20,163, respectively, p < .001). Conclusions: The results showed adherence to the ASCO Antiemesis Guidelines led to lower rates of CINV and lower costs. Although defining CINV by claims may tell an incomplete story, this study suggests that following the ASCO Antiemesis Guidelines may help both patients and payers of health care costs.