Background: There are various treatment modalities for metastatic breast cancer to the brain (MBC-b), with wide variation of reported outcomes. Methods: There were 1,513 patients (pts) with MBC-b treated at MD Anderson Cancer Center October 2009-December 2012. We reviewed medical records of the first consecutive 1015 and included 792 with confirmed brain metastases (BM). A Cox multivariate model was used to identify the effect of treatment on time-to-progression in the brain (TTP-b) and overall survival (OS). Results: Disease subtypes: ER+/HER2- (27%); ER+/HER2+ (16%); ER-/HER2+ (18%); ER-/HER2- (29%), missing (10%). Number of BM: 1 (20%), >1 (73%), missing (7%). Local treatment: metastasectomy (S) (13%), radio-surgery (SRS) (12%), whole-brain radiation (WBRT) (57%), combination of S/SRS with WBRT (11%), no treatment (7%). Systemic treatment: Any (64%), HER2 directed (24%). Median OS was 11.33 months(m) (4.4-25.8). Clinical characteristics associated with OS in multivariate analysis: ER+, HER2+, age < 60, ECOG 0-1, single BM, controlled systemic disease at time of BM and <3 treatment lines before BM. After correction for covariates, use of systemic therapy was associated with longer OS (HR 0.35 CI 0.20-0.60, p < 0.001) regardless of subgroup: HER2+ (19.9 vs 3.5m), ER+/HER2- (12.7 vs 2.2m), ER-/HER- (10.5 vs 2.3m). In pts receiving trastuzumab at diagnosis of BM, continuation of HER2 therapy increased OS (HR 0.44 CI 0.25-0.77, p = 0.004) regardless of agent used (lapatinib vs trastuzumab p=0.7). OS was the same for S and SRS (p=0.7) and either one increased OS (HR 0.41 CI 0.21-0.79 p=0.008). WBRT prolonged OS in multiple BM (HR 0.61 CI 0.38-0.96); Median TTP-b was 11.07m (5-24). WBRT added to S/SRS had longer TTP-b than either modality alone (17.6m vs 10.4m HR 0.56 CI 0.37-0.85 p=0.006). Use of systemic therapy after diagnosis of BM increased TTP-b (11.8 vs 5.1m HR 0.55 CI 0.33-0.92 p = 0.024), but there was no difference between agents used (lapatininib vs trastuzumab p=0.79; capecitabine vs others p= 0.96). Conclusions: WBRT improved local control when done after S/SRS. The use of chemotherapy after local therapy improved time to progression in the brain and survival.