Background: Pembrolizumab has received tumor-agnostic approval for the treatment of unresectable/metastatic solid tumors carrying a tumor mutational burden (TMB) >10 mut/Mb. The registrational KEYNOTE-158 study, however, did not include any patients with metastatic breast cancer (MBC). Here we present a retrospective study of patients with TMB-high MBC treated with immune checkpoint inhibition (ICI) and report real-world efficacy endpoints, including progression free survival as well as clinical and genomic characteristics that may be associated with duration of response. Methods: All patients with MBC treated with an ICI at MSK and with TMB-high tumors (>10 mut/Mb) assessed by tumor-normal targeted sequencing (MSK-IMPACT) were included. Clinicopathological and demographic data were obtained via the MSK Breast Cancer Translational Program. Mutational signatures were determined using the Signature Multivariate Analysis (SigMA) algorithm. Real world progression free survival (PFS) was determined clinically and analyzed using Kaplan-Meier estimates. Univariate and multivariate analyses were performed using Cox-proportional hazards models. Results: Of 688 patients with TMB-high breast cancer at MSKCC, 87 had received ICI-based therapy for estrogen receptor positive (ER+), triple negative breast cancer (TNBC), and HER2+ MBC. Of those, 45 patients were treated with ICI monotherapy (29 ER+, 11 TNBC, 5 HER2), 31 were treated with ICI + chemotherapy (12 ER+, 19 TNBC), and 11 were treated with combinations of ICI and targeted therapy (8 ER+, 1 TNBC, 2 HER2). Median age at time of ICI treatment across all patients was 60. ICI was the median 5^th line therapy for all patients (range 1-16). Median PFS of ICI for all patients was 3.17 months (95%CI 2.27-5.5). Multivariable analysis did not show statistically significant differences in PFS based upon treatment regimen (monotherapy vs. chemoIO HR 1.03, 95%CI 0.54-1.96, p= 0.92, monotherapy vs combination IO HR 1.66, 95%CI 0.69-4.02, p=0.26), ER status (ER- vs ER+, HR 1.20, 95%CI 0.63-2.28, p=0.57), or HER2 status (HER2- vs HER2+, HR 1.63, 95%CI 0.51-5.20, p=0.41. However, longer PFS was significantly associated with TMB>30 (HR 0.35, 95%CI 0.13-0.92, p=0.03) and dominant APOBEC signature score (APOBEC- vs APOBEC+, HR 0.49, 95%CI 0.25-0.98, p=0.04). Shorter PFS was significantly associated with later treatment line at the time of ICI exposure (continuous, HR 1.22, 95%CI 1.11-1.36, p=0.0001). Conclusions: In this heavily pretreated real-world cohort, ICI in TMB high MBC shows modest clinical activity. Our analysis suggests that ICI may be more effective in MBC patients that are less heavily pre-treated, have TMB>30, and have a predominantly APOBEC mutational signature. Further translational work is necessary to explore the mechanisms of these findings.