The invention provides a CD4 protein-resistant monoclonal antibody and an active fragment and an application thereof. The antibody can be used for preventing a human immunodeficiency virus (HIV) from invading cells through combination with a human CD4 protein. The antibody can be used for detecting, diagnosing, preventing and treating diseases in which CD4 cells are taken as target cells, particularly an acquired immunodeficiency syndrome caused by the HIV. The invention further provides a relevant hybrid tumor cell strain, a separated nucleic acid molecule, a small peptide, a medicinal composition comprising the monoclonal antibody, and a kit.