The introduction of the HIV aspartic peptidase inhibitors (HIV-PIs) has revolutionized the medical arena, since they have drastically reduced the number and the severity of opportunistic infections, including the protozoal diseases that afflict the HIV-infected individuals worldwide. HIV-PIs rapidly and profoundly diminish the viral load, which is paralleled by increase in the CD4+ T lymphocyte counts and stimulation of the survival and activation of neutrophil, monocyte and endothelial cells, culminating in a vigorous reduction in the number of deaths due to the AIDS, in the number of new cases of AIDS and in the number of hospitalization days. Many research groups around the globe are trying to decipher both the in vitro and in vivo antiprotozoal mechanisms behind the use of HIVPIs. These studies have been supported by the urgent need to discover novel active compounds able to treat incurable parasitoses, including three major neglected diseases: malaria, leishmaniasis and Chagas’ disease. The present review summarizes the recent advances on the effects of HIV-PIs against Plasmodium spp., Leishmania spp. and Trypanosoma cruzi.