It has been contended that limited data exist on sex-difference in immune response with vaccines in humans. However, a comprehensive search of the literature retrieved 97 studies with 14 vaccines influenza (7 studies), hepatitis A (15 studies), hepatitis B (50 studies), pnuemococcal polysaccaride (4 studies), diphtheria (4 studies), rubella (3 studies), measles (2 studies), yellow fever (3 studies), meningococcal A (1 study), meningococcal C (1 study), tetanus (1 study), brucella (1 study), Venezuelan equine encephalitis (1 study) and rabies (4 studies), with sex-difference in humoral (antibody) response. These differences are associated with sex-difference in the clinical efficacy of influenza, hepatitis A, hepatitis B, pneumococcal polysaccharide and diphtheria vaccines and significant adverse reactions with rubella, measles and yellow fever vaccines. The genesis of these differences is uncertain but not entirely related to gonadal hormones (differences are seen in pre-pubertal and post-menopausal subjects not on hormone replacement therapy) or female sex (males had greater serological response for pneumococcal, diphtheria, yellow fever, Venezuelan equine encephalitis and in some studies with rabies vaccine. As sex-difference in humoral immune response was seen with most vaccines which cover the spectrum of mechanisms by which infectious agents cause disease (mucosal replication, viral viraemia, bacterial bacteraemia, toxin production and neuronal invasion), it is mandatory that vaccine trialists recruit a representative sample of females and males to be able to assess sex-differences which may have clinical implications.