Adverse events following immunization (AEFI) are not uncommon, with injection site reactions (ISRs) being the most common. Predictors of injection site reactions are vaccine factors (antigen characteristics, antigen dose, dose number of antigen, antigen adjuvanting and type of diluent), vaccine administration factors (site and route of administration) and vaccinee factors (age and sex, the latter the subject of this review). 1,074 studies which reported ISRs were retrieved by searching of on line journals and databases. Analysis of these data for sex-difference was only reported in 57 studies, with 54 of these studies reporting a sex-difference (42 in subjects >17 years and 12 in subjects <17 years). In accord with the well documented greater pain sensitivity in females compared with males, in all studies with vaccines which reported pain during and post vaccination [hepatitis A, B, diphtheria/tetanus toxoid, diphtheria/tetanus/pertussis(DTaP and Tdap), anthrax and inactivated influenza], females reported a greater rate of pain than males. The pathophysiology of the sex-difference in local reactions (induration, tenderness, erythema, pruritus) following vaccination is clearly multifactorial with hypersensitivity reaction (type III, Arthus reaction-antigen/antibody immune complex formation), route of administration and hormonal factors being suggested. The data presented in this review demonstrate that studies of AEFI should recruit similar numbers of females and males and that these data should be analyzed for sex-difference. Additionally, unlike as at present, reporting of analysis of AEFI data by sex should become standard practice.