Biomphalaria spp. snails are intermediary hosts of Schistosoma mansoni, etiologic agent of intestinal schistosomiasis, one of the most important neglected tropical diseases. Biomphalaria straminea is an important intermediary host that possess a diferent phenotype to parasite infection but shows a large geographic distribution and high capacity of new ecologic niche invasion. Our purpose was to characterize for the frst time the diferentially expressed proteome in B. straminea during two times intervals after primary and secondary exposure to S. mansoni. The hemolymph was collected at 1 and 15 days after primary and secondary exposure of snails to the parasite. Total proteins were extracted and digested with trypsin. LC–MS/ MS label-free quantifcation was performed and analyzed using Maxquant and Perseus software. Proteins were identifed and annotated using Blast2GO tools. After 1 day of exposure, most of upregulated proteins are hemoglobin type 2, C and H type lectins, molecules related to cell adhesion, and response to oxidative stress. After 15 days, we found a similar pattern of upregulated proteins but some fbrinogen-related proteins (FREPs) and TEPs homologs were downregulated. Regarding the diferentially expressed proteins during secondary response, the principal immune-related proteins upregulated were C and H type lectins, cellular adhesion molecules, biomphalysin, and FREP3. We noted a several upregulated biological processes during both responses that could be the one of the key points of efcacy in the immune response to parasite. Our data suggests diferent immune mechanisms used by B. straminea snails challenged with S. mansoni.