Background: For postmenopausal women with hormone receptor positive (HR+) breast cancer, the optimal duration of extended endocrine therapy (EET), after completing 5 years of initial aromatase inhibitor (AI)–based adjuvant therapy, remains unclear. BCI [HOXB13/IL17BR (H/I)] is a gene expression-based biomarker that has been demonstrated to predict EET benefit in the MA.17 and Trans-aTTom studies in patients treated with adjuvant tamoxifen. The current study examined the ability of BCI (H/I) to predict endocrine benefit from 2.5 vs. 5 years of extended letrozole in the IDEAL trial. Methods: All patients with available tumor specimens were eligible for this blinded prospective-retrospective study. The primary endpoint was Recurrence-Free Interval (RFI). Median follow-up was 9.1 years from randomization. Kaplan-Meier and Cox proportional hazards regression analysis were used to analyze the differential benefit of EET with statistical significance of the interaction between BCI (H/I) and treatment assessed by likelihood ratio test. Results: 908 HR+ patients (73% pN+, median 59y, 45% pT1, 48% pT2, disease free at 2.5 years) were included, with 88% and 68% receiving prior treatment with an AI or chemotherapy, respectively. BCI by H/I status (High vs. Low) was significantly predictive of response from extended letrozole in the overall (N = 908) and pN+ (N = 664) cohorts. Notably, BCI (H/I) predicted EET benefit in patients that received any primary adjuvant therapy with an AI (N = 794). Treatment to biomarker interaction was significant in the overall (p = 0.045), pN+ (p = 0.029) and any prior AI (p = 0.025) cohorts, adjusted for age, pT stage, grade, nodal status, prior endocrine therapy and prior chemotherapy. Conclusions: Novel findings from this study demonstrate that BCI predicts endocrine benefit from extended letrozole in postmenopausal patients treated with primary adjuvant AI. These results support the growing body of evidence that BCI by H/I status predicts preferential endocrine response in distinct subgroups of patients, and further support its role as an important genomic tool to inform the risk-benefit regarding duration of extended endocrine therapy. Clinical trial information: NTR3077, BOOG 2006-05, Eudra-CT 2006-003958-16.