Fasciolosis caused by the liver fluke Fasciola hepatica is a worldwide spread parasitic disease of ruminants and is recognized as an emerging human disease. This work is focused on FhCY2, a member of cystatin superfamily, which is present in several tissues of F. hepatica and its excretory/secretory products. Structural and phylogenetic analyses revealed that FhCY2 belongs to stefins (type 1 cystatins). Stefins are typically intracellular, without signal sequence and without disulfides. However, FhCY2 breaks these rules, thus resembling members of extracellular type 2 cystatins. Our work shows that FhCY2 is an evolutionary adaptation to the absence of type 2 cystatins in the F. hepatica genome. FhCY2 is a broad-selective inhibitor of host cysteine cathepsins as well as secreted digestive cysteine cathepsins of F. hepatica, suggesting a dual role of FhCY2 in the physiological regulation of exogenous and endogenous proteolytic systems.