Background: Despite the broad spectrum of available therapies, HNSCC patients have poor outcome due to locoregional recurrence. Mechanisms responsible for immune suppression include activities of checkpoint receptors/ligands. HNSCCs with high expression levels of PD-L1 have especially poor outcome. Thus, PD-1 and PD-L1 inhibitors show potential as anticancer strategies. However, many patients with PD-L1+ HNSCC don’t benefit from checkpoint inhibitor therapy, suggesting that PDL-1 expression on tumors is not the only factor predictive of response. Tumor derived exosomes carry numerous immunosuppressive molecules and deliver them to recipient immune cells. We have demonstrated that elevated levels of circulating immunosuppressive exosomes play a key role in immune suppression and disease progression. Here, we show that surface PD-L1 on exosomes is responsible for these effects. Methods: Exosomes were isolated from plasma of 40 HNSCC patients by mini size exclusion chromatography, captured on beads using anti-CD63 Abs, stained for PD-1 and PD-L1 and analyzed by flow cytometry. Percentages of PD-L1+ and PD-1+ exosome/bead complexes were correlated with clinicopathological data. PD-L1^high or PD-L1^low exosomes were incubated with activated human CD8 T-cells ± PD-1 inhibitor and CD69 expression levels on T-cells were measured. Patients’ plasma was tested for soluble PD-L1 by ELISA. Results: The PD-L1 surface expression on exosomes correlated with patient’s disease activity, UICC stage and lymph node status with p values ranging from 0.0008-0.013. In contrast, plasma PD-L1 levels didn't correlate with any parameters. Exosome PD-1 levels were not informative. T-cell activation was inhibited (p < 0.03) by co-incubation with PD-L1^high but not PD-L1^low exosomes. This inhibition was reversed by adding a PD-1 inhibitor to T-cells prior to their incubation with exosomes. Conclusions: We show that PD-L1 levels on exosomes, but not plasma levels, correlated with clinicopathological data in HNSCC patients. Blocking of PD-L1+ exosomes signaling to PD-1+ T-cells with anti-PD-1 Ab attenuated immune suppression. Altogether, PD-L1+ exosomes serve as useful metrics of disease and immune activity in HNSCC patients.