Background: Management of metastatic breast cancer to the brain (MBC-B) is mainly surgery and/or radiation. The efficacy of systemic therapy remains controversial. Methods: Out of 1514 consecutive patients (pts) with MBC-B treated at MDACC October 1999-December 2012, 882 had complete data and were included in this retrospective study. We used a Cox multivariate model to identify the effect of any systemic therapy on time-to-progression in the brain (TTP-B) and overall survival (OS). Results: Disease subtypes: ER+/HER2- (26%) ER+/HER2+ (17%); ER-/HER2+ (20%); ER-/HER2- (33%), missing (4%). Number of brain metastasis (BM): 1 (24%), > 1 (67%), concurrent LMD (8%), missing (1%). Local treatment: metastasectomy (S) (5%), stereotactic radio-surgery (SRS) (14%), whole-brain radiation (WBRT) (58%), combination S/SRS with WBRT (12%); no treatment (11%). Subsequent systemic therapy was given to 679 pts (77%). Median OS was 9.7 months (m) (4.0-21.9). Systemic therapy prolonged OS (HR 0.44 CI 0.36-0.52 p < 0.001) for all subgroups: HER2+ (17.8 vs 3.3m); ER+/HER2- (10.7 vs 2.3m); ER-/HER2- (8.4 vs 2.4m). Other factors associated with OS: ER+, HER2+, age < 60, ECOG 0-1, single BM, controlled extra-cranial disease, local therapy to the brain, less than 3 lines of therapy prior to diagnosis of BM. Disease progression in the brain was documented in 359 pts (40.7%). Median TTP-B was 6.8m (3.7-12.1). Systemic therapy prolonged TTP-B (7 vs 4.5m; HR 0.58 CI 0.40-0.84 p = 0.005). Other factors associated with TTP-B: ER+, HER2+, single BM, and local therapy to the brain. In pts receiving anti-HER2 based therapy at diagnosis of BM, continuation of anti-HER2 agents prolonged TTP-B (HR 0.41 CI 0.23-0.72, p < 0.001) and OS (HR 0.41 CI 0.28-0.59, p < 0.001). Lapatinib-based was not superior to trastuzumab-based therapy and capecitabine was not superior to other cytotoxic agents. Pts who were on systemic therapy at diagnosis of BM and had controlled extra-cranial disease did not benefit from switching to non-cross-resistant agents. Conclusions: In patients with breast cancer metastatic to the brain, systemic chemotherapy was associated with better control in the brain and longer survival.