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Background: MicroRNAs (miRNAs) are a class of short non-coding RNA that play important roles in disease processes in animals and are present in a highly stable cell-free form in body fluids. Here, we examine the capacity of host and parasite miRNAs to serve as tissue or serum biomarkers of Schistosoma mansoni infection. Methods/Principal Findings: We used Exiqon miRNA microarrays to profile miRNA expression in the livers of mice infected with S. mansoni at 7 weeks post-infection. Thirty-three mouse miRNAs were differentially expressed in infected compared to naïve mice (>2 fold change, p<0.05) including miR-199a-3p, miR-199a-5p, miR-214 and miR-21, which have previously been associated with liver fibrosis in other settings. Five of the mouse miRNAs were also significantly elevated in serum by twelve weeks post-infection. Sequencing of small RNAs from serum confirmed the presence of these miRNAs and further revealed eleven parasite-derived miRNAs that were detectable by eight weeks post infection. Analysis of host and parasite miRNA abundance by qRT-PCR was extended to serum of patients from low and high infection sites in Zimbabwe and Uganda. The host-derived miRNAs failed to distinguish uninfected from infected individuals. However, analysis of three of the parasite-derived miRNAs (miR-277, miR-3479-3p and bantam) could detect infected individuals from low and high infection intensity sites with specificity/sensitivity values of 89%/80% and 80%/90%, respectively. Conclusions: This work identifies parasite-derived miRNAs as novel markers of S. mansoni infection in both mice and humans, with the potential to be used with existing techniques to improve S. mansoni diagnosis. In contrast, although host miRNAs are differentially expressed in the liver during infection their abundance levels in serum are variable in human patients and may be useful in cases of extreme pathology but likely hold limited value for detecting prevalence of infection. Author Summary: Schistosomiasis is a chronic disease caused by blood flukes that affects over 200 million people worldwide, of which 90% live in Sub-Saharan Africa. In the field setting schistosomiasis caused by S. mansoni is diagnosed by detection of parasite eggs in stool samples using microscopic techniques. Here we investigate the potential of microRNAs (miRNAs), a class of short noncoding RNAs, to act as biomarkers of S. mansoni infection. We have identified a specific subset of murine miRNAs whose expression is significantly altered in the liver between 6–12 weeks post infection. However their abundance in serum is not significantly different between naïve and S. mansoni-infected mice until twelve weeks post infection and they do not display consistent differential abundance in the serum of infected versus uninfected humans. In contrast, three parasite-derived miRNAs (miR-277, bantam and miR-3479-3p) were detected in the serum of infected mice and human patients and the combined detection of these miRNAs could distinguish S. mansoni infected from uninfected individuals from low and high infection intensity areas with 89%/80% or 80%/90% specificity/sensitivity, respectively. These results demonstrate that miRNAs of parasite origin are a new class of serum biomarker for detecting S. mansoni and likely other helminth infections. [ABSTRACT FROM AUTHOR]