Head and neck squamous cell carcinomas (HNSCC) are highly immunosuppressive, and tumor-associated macrophages comprise a major part in HNSCC tumor microenvironments. Here, we investigate the effects induced by small extracellular vesicles (sEVs) of HNSCC patients on primary macrophages. sEVs were isolated from plasma by size-exclusion chromatography. Internalization of PKH26-labeled sEVs was shown and mass spectrometry analysis was performed on HNSCC sEVs and sEV-treated macrophages. NF-κB activation was investigated by western blot, p65 translocation assay and proteome profiler. Downstream, mRNA and protein levels of cytokines and chemotaxis of T cells were investigated. Results from proteomic analysis revealed time-dependent modulation of the NF-κB signaling pathway, which was confirmed by other methods and caused altered downstream cytokine expression in macrophages. sEVs from HNSCC patients positive for human papilloma virus showed increased uptake of sEV and NF-κB activation. In conclusion, HNSCC sEVs significantly influenced macrophage proteome and NF-κB signaling, providing a potential target specifically targeting HPV(+), but not HPV(-) HNSCC.