Fonsecaea pedrosoi is the most frequent dematiaceous fungus that causes chromoblastomycosis, a subcutaneous chronic infection human disease common in tropical and subtropical countries. This infection is characterized by nodulo-verrucous lesions that are notoriously recalcitrant to antifungal therapy. There is accumulating evidence showing the direct involvement of proteases in fungus-host interactions, which includes digestion of exogenous proteins for nutrition purposes, invasion of host cells and tissues, and inactivation of host proteins that are detrimental to fungus survival. In the present work, we examined the effect of different HIV aspartyl peptidase inhibitors on the peptidase extracellularly released by F. pedrosoi as well as on the growth. Conidia grown under chemically defined conditions (Czapek-Dox medium) secreted aspartyl peptidase that cleaved soroalbumin bovine (BSA) reaching a maximum activity at pH 4.0. HIV aspartyl peptidase inhibitors as indinavir, saquinavir, ritonavir and nelfinavir (50, 100 and 200 mM) were able inhibit in a dose-dependent manner the secretory peptidase of F. pedrosoi, while the cellular growth was totally abolished when conidial cells were pretreated with saquinavir and nelfinavir at 100 mM. By means of transmission electron microscopy we detected some ultrastructural alterations including increase of invaginations of plasmatic membrane, disorder and detachment in the cell wall, enlargement of intracellular vacuoles, abnormal division disfiguring regular conidia morphology and breakage of cell wall starting from extracellular environmental, which culminated in the fungal death. The pathogenicity mechanisms express by F. pedrosoi are completely unknown. However, we suggest a possible involvement of extracellular proteolytic enzymes in essential process to this fungal growth. In this context, HIV proteinase inhibitors could be a potential target for the treatment of chromoblastomycosis.