Influenza remains a major cause of morbidity and mortality, particularly in at-risk groups where vaccination reduces complications of infection but is not universally protective. In order to determine whether human leukocyte antigen (HLA) class II polymorphisms modulate anti-influenza antibody responses to vaccination, a cohort of HLA-typed at-risk donors was investigated. The subjects were recruited from a single urban family practice. Hemagglutination-inhibition (HAI) titers were measured immediately before and 28 days after subunit vaccination. Nonresponsiveness was defined as failure to mount an HAI response to any component of the trivalent influenza vaccine. When the nonresponders and responders with HLA class II were compared, the nonresponder group had more HLA-DRB1*07-positive donors (13/32 vs. 6/41 responders; P=.016, Fisher's exact test) and fewer HLA-DQB1*0603-9/14-positive donors (2/32 vs. 14/41 responders; P=.0045). Thus, polymorphisms in HLA class II molecules appear to modulate antibody responses to influenza vaccination.