The author has summarized the history of discovery, the mechanism and the clinical significance of antibody-dependent enhancement (ADE) of HIV infection. ADE has two major forms: (a) complement-mediated antibody-dependent enhancement (C-ADE) and (b) complement-independent Fc receptor-dependent ADE (FcR-ADE). The most important epitope responsible for the development of C-ADE-mediating antibodies is present in the immunodominant region of gp41 while antibodies mediating FcR-ADE react mainly with V3 loop of gp120. There are at least three fundamentally different hypotheses for the explanation of ADE in vitro: (a) increased adhesion of HIV-antibody-(complement) complexes to FcR or complement receptor carrying cells; (b) facilitation of HIV-target cell fusion by complement fragment deposited on the HIV-virions and (c) complement activation products may have a non-specific stimulatory effect on target cells resulting in enhanced virus production. FcR-ADE and C-ADE have been measured in vitro mostly by using FcR-carrying and complement receptor-carrying cell lines, respectively; no efforts have been made to standardize these methods. Several data support the possible clinical significance of FcR-ADE and C-ADE: (a) Cross-sectional and longitudinal studies indicate a correlation between the amounts of FcR-ADE and C-ADE-mediating antibodies and clinical, immunological and virological progression of the HIV-disease; (b) ADE may facilitate maternal–infant HIV-1 transmission; (c) According to experiments in animal models, ADE are present and may modify the course of SIV (simian immunodeficiency) infection as well. The author raises a new hypothesis on the mechanism of the in vivo effect of C-ADE. According to the hypothesis, C-ADE-mediating antibodies exert their effect through enhancement of HIV propagation and consequent facilitation of the progression of HIV disease. Finally, according to observations from animal experiments and human clinical trials it cannot be excluded that ADE-mediating antibodies may develop, diminish the beneficial effect or may be harmful in volunteers vaccinated with HIV-1 candidate vaccines.