We analyzed the relationship between host gene polymorphisms and responses in recipients of inactivated influenza vaccine, who were classified into poor, normal, or adverse response groups. The frequency of the mannose-binding lectin-2 codon 54 allele was significantly different among the 3 types of responders, with a decreased odds ratio for the development of poor or adverse responses (P=.033). There was no statistical relationship between responses and either tumor necrosis factor- alpha or interleukin (IL)-10 promoter polymorphisms among the 3 response groups. When poor and normal responses were combined, the -1082 A allele in the IL-10 promoter conferred a significantly decreased risk of the development of adverse responses (P=.041). These data indicate that host polymorphisms play a role in determining responses to influenza vaccine.