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Simple Summary: Infectious diseases are a matter of concern worldwide, as recently evidenced by the COVID-19 pandemic. However, in many instances, pathogens develop slowly, and patients discover they are ill even years after they were infected. This is the case of diseases caused by tapeworm parasites, such as alveolar (AE) and cystic (CE) echinococcosis. Both AE and CE are produced by the growth of parasite larvae in organs of the host, mainly the liver. Despite the life cycles of these pathogens having been elucidated over 100 years ago, current diagnostic techniques cannot determine parasite viability during infection or treatment follow-up. Recently, a novel group of diagnostic molecules, namely small RNAs (sRNAs), have emerged with promising results in several pathologies. sRNAs are short nucleic acids expressed and secreted by cells; they can be detected in fluids such as serum, and their circulating levels are altered during diverse pathological states. Here, we characterized the profile of circulating sRNAs in patients with AE and CE to identify novel biomarkers that may aid in medical decisions. As a result, a panel of 20 candidate markers related to each pathogen and/or liver lesion were identified, which resulted in valuable knowledge to improve the diagnosis of these parasitic diseases. Alveolar (AE) and cystic (CE) echinococcosis are two parasitic diseases caused by the tapeworms Echinococcus multilocularis and E. granulosus sensu lato (s. l.), respectively. Currently, AE and CE are mainly diagnosed by means of imaging techniques, serology, and clinical and epidemiological data. However, no viability markers that indicate parasite state during infection are available. Extracellular small RNAs (sRNAs) are short non-coding RNAs that can be secreted by cells through association with extracellular vesicles, proteins, or lipoproteins. Circulating sRNAs can show altered expression in pathological states; hence, they are intensively studied as biomarkers for several diseases. Here, we profiled the sRNA transcriptomes of AE and CE patients to identify novel biomarkers to aid in medical decisions when current diagnostic procedures are inconclusive. For this, endogenous and parasitic sRNAs were analyzed by sRNA sequencing in serum from disease negative, positive, and treated patients and patients harboring a non-parasitic lesion. Consequently, 20 differentially expressed sRNAs associated with AE, CE, and/or non-parasitic lesion were identified. Our results represent an in-depth characterization of the effect E. multilocularis and E. granulosus s. l. exert on the extracellular sRNA landscape in human infections and provide a set of novel candidate biomarkers for both AE and CE detection. [ABSTRACT FROM AUTHOR]