Schistosome worms infect over 200 million people worldwide. They live in the host's bloodstream and alter host immunity. Epidemiological data suggest that males and females have different responses to schistosome infection, but the effect of sex on systemic response is undetermined. Our objective was to characterize differences in peripheral blood transcriptional profiles in people with or without active infection, and to determine whether this signature differs between males and females.Messenger RNA was isolated using poly(A) selection and sequenced on an Illumina Hi-Seq4000 platform. Transcripts were aligned to the human hg19 reference genome and counted with the HTSeq package. Genes were compared for differential expression using DESeq2. Ingenuity Pathway Analysis was used to identify gene networks altered in the presence of We enrolled 33 participants from villages in rural Tanzania where is endemic. After correction for multiple comparisons, we observed 383 differentially-expressed genes between those with and without infection when sex was included as a covariate. Heat-mapping of the genes with greater than 1.5-fold differences in gene expression revealed clustering by infection status. Top networks included development, cell death and survival, cell signaling, and immunologic disease pathways.We observed a distinct whole blood transcriptional profile, as well as differences in men and women, with infection. Additional studies are needed to determine the clinical effects of these divergent responses. Attention to sex-based differences should be included in studies of human schistosome infection.