This study investigates the influence of human papillomavirus (HPV) on the proteomic content of exosomes derived from head and neck squamous cell carcinoma (HNSCC) cell lines. Label-free quantitative proteomics was used to analyze exosomes and parental cells from HPV16-positive (93VU147T, UDSCC2) and HPV-negative (OCT-1) HNSCC cell lines. Raw LC-MS/MS data were acquired to study differentially exported proteins, with emphasis on exosomal cargo variation and its functional implications.