PD-L1+ tumor-derived extracellular vesicles (TEVs) cause systemic immunosuppression and possibly resist to anti-PD-L1 antibody (αPD-L1) blockade. However, whether and how PD-L1+ TEVs mediate αPD-L1-therapy resistance is unknown. Here, we show that PD-L1+ TEVs massively decoy αPD-L1 and that TEV-bound αPD-L1 is more rapidly cleared by macrophages, causing insufficient blockade of tumor PD-L1 and subsequent αPD-L1-therapy resistance. Either an increased dose of αPD-L1 or macrophage depletion mediated by clinical drug Pexidartinib abolishes αPD-L1-therapy resistance. In the treatment cycle with the same total treatment dose of αPD-L1, high-dose and low-frequency treatment has better antitumor effects than low-dose and high-frequency treatment, induces stronger antitumor immune memory, and eliminates αPD-L1-therapy resistance. Furthermore, increased doses of αPD-L1 and αPD-1 have comparable antitumor effects, but αPD-L1 amplify fewer PD-1+ Treg cells that are responsible for tumor hyperprogression. Altogether, our results reveal a TEV-mediated mechanism of αPD-L1-specific therapy resistance, thus providing promising strategies to improve αPD-L1 efficacy.