The TGF-β-regulated Chloride Intracellular Channel 4 (CLIC4) is an essential participant in the formation of breast cancer stroma. Here, we used data available from the TCGA and METABRIC datasets to show that CLIC4 expression was higher in breast cancers from younger women and those with early-stage metastatic disease. Elevated CLIC4 predicted poor outcome in breast cancer patients and was linked to the TGF-β pathway. However, these associations did not reveal the underlying biological contribution of CLIC4 to breast cancer progression. Constitutive ablation of host Clic4 in two murine metastatic breast cancer models nearly eliminated lung metastases without reducing primary tumor weight, while tumor cells ablated of Clic4 retained metastatic capability in wildtype hosts. Thus, CLIC4 was required for host metastatic competence. Pre- and post-metastatic proteomic analysis identified circulating pro-metastatic soluble factors that differed in tumor-bearing CLIC4-deficient and wildtype hosts. Vascular abnormalities and necrosis increased in primary tumors from CLIC4-deficient hosts. Transcriptional profiles of both primary tumors and pre-metastatic lungs of tumor-bearing CLIC4-deficient hosts were consistent with a microenvironment where inflammatory pathways were elevated. Altogether, CLIC4 expression in human breast cancers may serve as a prognostic biomarker; therapeutic targeting of CLIC4 could reduce primary tumor viability and host metastatic competence. Author summary: CLIC4, a member of a highly conserved CLIC gene family, contributes to the pathogenesis of several human diseases. We show that elevated CLIC4 expression in human breast cancers predicts early invasion and poor outcome in women. Further, in murine models of breast cancer, CLIC4 in the host microenvironment is required for lung metastasis. In the absence of host CLIC4, the microenvironment of the primary tumor and the pre-metastatic lungs is unfavorable for tumor viability and lung colonization. These findings introduce CLIC4 as a potential therapeutic target against a host protein to prevent metastatic spread in breast cancer. [ABSTRACT FROM AUTHOR]