The co-evolutionary dynamics that exist in many host-parasite interactions sometimes lead to a compatibility polymorphism, of which the molecular bases are unknown. To identify key molecules involved in this phenomenon in the S. mansoni/B. glabrata model, we developed a comparative proteomics approach for the larval stages that interact with the invertebrate host. The comparison of the proteomes of compatible and incompatible parasite strains led to the identification of a newfamily of schistosome antigens that share molecular characteristics with the molecules of the mucin family. In particular, they possess a domain containing a variable number of tandem repeats (VNTR). The pronounced polymorphism of these proteins, that distinguishes compatible and incompatible parasite strains, led us to further investigate the role that this protein family plays in the compatibility polymorphism in our model. In the present study, we examine precursor structure, report analysis of mucin-like expression and describe their polymorphism. Our data show that these proteins share structural characteristics with highly glycosylated secreted mucins. The proteins are (i) only expressed in larval stages that interact with the mollusc, (ii) located in the apical gland of miracidia and sporocysts and (iii) secreted and released in excretion–secretion products. Finally, we show that these mucins display a high degree of polymorphism and that extensive differences are observed between S. mansoni strains. These different characteristics led us to name this novel gene family “S. mansoni polymorphic mucins” (Sm PoMuc).