The co-evolutionary dynamics that exist in host–parasite interactions sometimes lead to compatibility polymorphisms, the molecular bases of which are rarely investigated. To identify key molecules that are involved in this phenomenon in the Schistosoma mansoni/Biomphalaria glabrata model, we developed a comparative proteomics approach using the larval stages that interact with the invertebrate host. We used qualitative and quantitative analyses to compare the total proteomes of primary sporocysts from compatible and incompatible parasite strains. The differentially expressed proteins thus detected belong to three main functional groups: (i) scavengers of reactive oxygen species, (ii) components of primary metabolism, and (iii) mucin-like proteins. We discuss the putative roles played by these protein families as determinants of compatibility polymorphism. Since mucins are known to play key roles in the host–parasite interplay, we consider the newly discovered S. mansoni mucin-like proteins (SmMucin-like) as the most promising candidates for influencing the fate of host–parasite interactions. An analysis of their expression is presented in a paper published in the same journal issue.