Malignant cells show increased invasion potency in vitro and in vivo. This process is considered to be mediated by matrix-metalloproteases (MMPs). Hypoxia-inducible factor-2α (HIF-2α) may upregulate MMP-2 expression; however, little is known about the correlation between HIF-2α and MMP-2 expressions in breast cancer. The current study investigated this correlation immunohistochemically according to various clinical and pathological features in 102 paraffin-embedded archival tissue block specimens from patients with breast cancer. HIF-2α and MMP-2 expression was detected in 60.8% (62/102) and 65.7% (67/102) of tumor samples, respectively. HIF-2α expression was significantly correlated with tumor size (P = 0.019), lymph node involvement (P = 0.035), and metastasis (P = 0.035). MMP-2 expression was significantly associated with lymph node involvement (P = 0.043) and metastasis (P = 0.003). Univariate analyses revealed that HIF-2α (P = 0.001) and MMP-2 (P = 0.000) expressions were significantly associated with a poorer survival rate, as well as tumor size, lymph node invasion, and distant metastasis. Multivariate analysis revealed that HIF-2α (P = 0.003) and the T-stage (P = 0.000) were independent prognostic factors of overall survival. Spearman correlation analysis revealed that HIF-2α and MMP-2 expressions were significantly correlated (r = 0.990; P = 0.041). These results suggest that high HIF- 2α expression is associated with poor overall survival in patients with breast cancer, indicating that HIF-2α could be a valuable marker of breast cancer progression.