Males and females differ in their immunological responses to viral and vaccine antigens, with females typically mounting higher immune responses than males. These sex-based immunological differences contribute to variation in susceptibility to infectious diseases and responses to vaccines in males and females. The intensity and prevalence of viral infections are typically higher in males, whereas disease outcome can be worse for females, which in many cases is caused by an exaggerated immune response that damages tissue and causes pathology. In response to vaccines, females mount higher immune responses and experience more adverse reactions than males. Several variables should be considered when evaluating male/female differences in responses to viral infection and treatment: these include age, hormones, genes, and gender-specific factors related to access to, and compliance with, treatment. Knowledge that the sexes differ in their responses to infectious diseases and vaccines should influence the recommended course of action differently for males and females.