Vaccination is a proven public health initiative, however it is imperative in the context of increasing concerns about vaccine induced adverse reactions and a decreasing incidence of diseases they prevent that the optimal route for their administration is defined. Traditionally all vaccines were given by subcutaneous injection until it was recognized that adjuvanted vaccines given via this route induced an unacceptable rate of injection site reaction. Evidence-based medicine has been championed as a way of improving the quality of patient care. Application of this methodology to the route of administration of vaccines demonstrates that vaccines should be given by intramuscular injection in preference to subcutaneous injection as the intramuscular route is associated with better immune response and a lower rate of injection site reaction. The basis of this superiority is discussed.