The first thrombocytopenia cases related to the human immunodeficiency virus (HIV) were described even before its isolation in 1983. Subsequently, multiple mechanisms have been proposed to elucidate the etiology of thrombocytopenia. In addition to other types of cytopenia affecting patients with HIV, thrombocytopenia is observed in about 10–50% HIV patients as one of the first clinical signs of infection. Thus, in this review we aim to summarize the mechanisms proposed for thrombocytopenia since the discovery of HIV, and especially the innovations in the field in recent years. Among the different mechanisms suggested for HIV-related thrombocytopenia, there is emphasis on the accelerated destruction of platelets (PLTs) due to the action of immune complexes, and the presence of anti-PLT and anti-HIV antibodies that cross-react with the PLT membrane. There are also secondary causes of thrombocytopenia, such as the effect of drugs and opportunistic diseases associated with HIV.