Abstract Regulatory T cells (Tregs) impede effective antitumor immunity. However, the role of Tregs in clinical outcomes of patients with triple-negative breast cancer (TNBC) remains controversial. Here, we found that an immunosuppressive TNBC microenvironment is marked by an imbalance between effector αβCD8+ T cells and Tregs harboring hallmarks of highly suppressive effector Tregs (eTregs). Intratumoral eTregs strongly expressed PD-1 and persisted in patients with TNBC resistant to PD-1 blockade. Importantly, CD25 was the most selective surface marker of eTregs in primary TNBC and metastases compared with other candidate targets for eTreg depletion currently being evaluated in trials for patients with advanced TNBC. In a syngeneic TNBC model, the use of Fc-optimized, IL-2 sparing, anti-CD25 antibodies synergized with PD-1 blockade to promote systemic antitumor immunity and durable tumor growth control by increasing effector αβCD8+ T cell/Treg ratios in tumors and in the periphery. Together, this study provides the rationale for clinical translation of anti-CD25 therapy to improve PD-1 blockade responses in patients with TNBC.