Abstract Myeloproliferative neoplasms (MPNs) are associated with immune dysregulation and increased susceptibility to infection, emphasizing the importance of vaccination for patients. This pilot study evaluated immune responses to influenza vaccination in MPN patients compared with healthy donors using mass cytometry and serology. We observed diminished CXCR5+ B‐cell, CXCR3+ T‐cell, activated CD127+ memory T‐cell subsets, and a trend toward lower hemagglutinin inhibition titer in MPN patients. These results indicate that patients with MPN exhibit distinct responses to influenza vaccination suggestive of impaired migration to lymphoid organs and T‐cell maturation which may impact the development of protective immunity.