Echinococcosis is a parasitic disease caused by the metacestodes of Echinococcus spp. The disease has a long latent period and is largely underdiagnosed, partially because of the lack of effective early diagnostic approaches. Using liquid chromatography-mass spectrometry, we profiled the serum-derived extracellular vesicles (EVs) of E. multilocularis-infected mice and identified three parasite-origin proteins, thioredoxin peroxidase 1 (TPx-1), transitional endoplasmic reticulum ATPase (TER ATPase), and 14-3-3, being continuously released by the parasites into the sera during the infection via EVs. Using ELISA, both TPx-1 and TER ATPase were shown to have a good performance in diagnosis of experimental murine echinococcosis as early as 10 days post infection and of human echinococcosis compared with that of control. Moreover, TER ATPase and TPx-1 were further demonstrated to be suitable for evaluation of the prognosis of patients with treatment. The present study discovers the potential of TER ATPase and TPx-1 as promising diagnostic candidates for echinococcosis. Author summary: Echinococcosis, also known as hydatid disease, is one of the neglected zoonotic diseases. Echinococcus multilocularis and Echinococcus granulosus sensu latu are the causative agents responsible for alveolar echinococcosis and cystic echinococcosis, respectively. Alveolar echinococcosis is mainly endemic in the areas of the northern hemisphere, whereas cystic echinococcosis has a worldwide distribution. The disease has a long latent period of up to 5 to 10 years and is largely underdiagnosed, partially due to the lack of effective early diagnostic approaches. In recent years, an emerging role of EVs in intercellular communication and diagnosis has been recognized. Here, we employed a proteomic approach to identify parasite-derived proteins in the serum EVs from E. multilocularis-infected mice and assessed their diagnostic values. This study signify the role of EVs for the identification of diagnostic candidates by the discovery of two identified proteins, TER ATPas and TPX-1. First results indicate their diagnostic and prognostic values in experimental murine and human echinococcosis. [ABSTRACT FROM AUTHOR]