Background: Randomized controlled trial (RCT) meta-analysis data have shown a significantly greater disease-free survival (DFS) benefit with aromatase inhibitors than TAM in patients with HR+/HER2− EBC. Here we compare real-world outcomes in patients with HR+/HER2− EBC who received adjuvant endocrine therapy (ET) with NSAIs or TAM. Methods: This was a retrospective analysis of ConcertAI’s deidentified electronic medical records data set of patients treated at US academic and community oncology clinics from January 1, 1995 to April 30, 2021. The cohort included patients with stage II-III (if IIIB or IIIC, confirmation was required on residual tumor status) HR+/HER2− EBC who underwent surgery and initiated adjuvant ET (excluding those who switched classes of ET); ovarian function suppression (OFS) was permitted. Menopausal status was determined using age (≥ 50 years) as a proxy for undocumented status. Invasive DFS (IDFS; risk of disease recurrence, death, or second primary tumor), distant DFS (DDFS; risk of distant recurrence, death, or second primary tumor), and overall survival (OS; risk of death) were assessed and defined as the time interval between start of ET and first event. Multivariate Cox regression analyses were performed, adjusting for age, stage, Charlson Comorbidity Index, and prior adjuvant or neoadjuvant chemotherapy for the ET cohort. Results: Of the total 3133 patients analyzed, 2507 were included in this analysis (NSAI ± OFS, n = 1854; TAM ± OFS, n = 653). Among these patients, the median (range) age was 59.5 (22.8-86.6) years, 25.4% were premenopausal, and 56.2% had tumor node involvement. The mean (SD) time to ET discontinuation was 46.2 (35.9) months overall and was similar between the NSAI and TAM cohorts. Reasons for ET discontinuation were undocumented or missing from the database for 76.8% of patients. Multivariate Cox regression analyses suggested a significant risk reduction with NSAIs vs TAM, with a 17% reduction in risk of an IDFS event (hazard ratio [HR], 0.83 [95% CI, 0.69-0.98]) and an 18% reduction in risk of a DDFS event (HR, 0.82 [95% CI, 0.69-0.98]). Although there were few events, OS analysis suggested a numerical trend favoring NSAIs over TAM, with a 12% reduction in risk of death (HR, 0.88 [95% CI, 0.69-1.13]). Conclusions: This real-world data analysis revealed a reduction in risk of IDFS and DDFS events with adjuvant NSAIs vs TAM in patients with HR+/HER2− EBC. Collectively, RCT and real-world data demonstrate greater benefit with adjuvant NSAIs vs TAM with respect to risk of recurrence in this patient population.