Antibody-dependent enhancement (ADE) is a phenomenon in which antibodies produced in the body after infection or vaccination may enhance subsequent viral infections in vitro and in vivo. Although rare, symptoms of viral diseases are also enhanced by ADE following infection or vaccination in vivo. This is thought to be due to the production of antibodies with low neutralizing activity that bind to the virus and facilitate viral entry, or antigen–antibody complexes that cause airway inflammation, or a predominance of T-helper 2 cells among the immune system cells which leads to excessive eosinophilic tissue infiltration. Notably, ADE of infection and ADE of disease are different phenomena that overlap. In this article, we will describe the three types of ADE: (1) Fc receptor (FcR)-dependent ADE of infection in macrophages, (2) FcR-independent ADE of infection in other cells, and (3) FcR-dependent ADE of cytokine production in macrophages. We will describe their relationship to vaccination and natural infection, and discuss the possible involvement of ADE phenomena in COVID-19 pathogenesis.