Influenza A and B viruses are negative-strand RNA viruses that cause regular outbreaks of respiratory disease and substantially impact on morbidity and mortality. Our primary defense against the influenza virus infection is provided by neutralizing antibodies that inhibit the function of the virus surface coat proteins hemagglutinin and neuraminidase. Production of these antibodies by B lymphocytes requires help from CD4+ T cells. The most commonly used vaccines against the influenza virus comprise purified preparations of hemagglutinin and neuraminidase, and are designed to induce a protective neutralizing antibody response. Because of regular antigenic change in these proteins (drift and shift mutation), the vaccines have to be administered on an annual basis. Current defense strategies center on prophylactic vaccination of those individuals who are considered to be most at risk from the serious complications of infection (principally individuals aged >65 years and those with chronic respiratory, cardiac, or metabolic disease). The clinical effectiveness of influenza virus vaccination is dependent on several vaccine-related factors, including the quantity of hemagglutinin within the vaccine, the number of doses administered, and the route of immunization. In addition, the immunocompetence of the recipient, their previous exposure to influenza virus and influenza virus vaccines, and the closeness of the match between the vaccine and circulating influenza virus strains, all influence the serologic response to vaccination.However, even when these vaccines are administered to young fit adults a proportion of individuals do not mount a significant serologic response to the vaccine. It is not clear whether these nonresponding individuals are genetically pre-programmed to be nonresponders or whether failure to respond to the vaccine is a random event. There is good evidence that nonresponsiveness to hepatitis B vaccine, another purified protein vaccine, is at least partially modulated by an individual's human leucocyte antigen (HLA) alleles. Because CD4+ T cells, which control the neutralizing antibody response to influenza virus, recognize antigens in association with HLA class II molecules, we recently conducted a small study to investigate whether there was any association between HLA class II molecules and nonresponsiveness to influenza virus vaccination. This work revealed that the HLA-DRB1*0701 allele was over represented among persons who fail to mount a neutralizing antibody response. This preliminary finding is important because it potentially identifies a group who may not be protected by current vaccination strategies. Further investigation into the role of HLA polymorphisms and nonresponse to influenza virus vaccination, and vaccination against viruses in general, is clearly required.