The majority of estrogen receptor positive (ER+) breast cancers (BC) express androgen receptors (AR). In our prior trial for women with heavily pretreated metastatic ER+/HER2- breast cancer (BC), fulvestrant (Fulv) combined with the anti-androgen enzalutamide showed clinical benefit. Short PFS was associated with activation of the mTOR pathway. We also conducted a randomized phase II trial for women with ER+/HER2- primary BC T2 or greater, with either Fulv alone or with enzalutamide (Combo) given for 4 months prior to surgery. Biopsies obtained at study entry (baseline), after 4 weeks on therapy (W5), and at surgery were obtained. IHC for ER/PR/AR/GR and Ki67, gene expression, and multiplex IF for immune cells was performed as well as reverse phase phosphoprotein assay (RPPA). Combo arm showed reduced residual tumor at time of surgery as measured by modified preoperative endocrine predictive index (PEPI) score: Combo arm PEPI=0 (24%) vs Fulv (8%). Odds of response were 4.6-fold higher (95% CI: 0.9-22) for patients with invasive lobular cancer (IDC) vs invasive ductal (IDC). AR protein was reduced by time of surgery in the Combo arm only (P0 (P<0.05) and in Ki67 responders vs non-responders (p<0.02). RPPA indicated that AR and pS650AR decreased significantly more from BL to W5 in ILC versus IDC as did cell cycle, and metabolism proteins. While ER-response and cell division gene sets decreased in tumors from both arms, Combo treated tumors uniquely showed significant enrichment of immune activation genes sets. Tertiary lymphoid structures (TLS) per area surrounding resected tumor were higher in Combo vs Fulv arm, near PEPI=0 (P<0.03) tumors and in ILC vs IDC (P<0.059). T regs were reduced in the Combo arm (p<0.0002) and in Ki67 responders (p<0.004). Tumor-associated macrophages decreased in Combo arm (p<0.0001) and PEPI=0 tumors (p<0.0005). AR inhibition combined with Fulv activates the immune system in ER+ BC, particularly in ILC.