The glycoproteins secreted by Schistosoma mansoni cercariae and eggs play a key role in parasite transmission to and from the mammalian host. We used secreted preparations from these two life cycle stages to characterize the reactivity of sera from baboons exposed to normal and/or attenuated cercariae, in comparison with somatic antigen preparations and defined glycan epitopes. Periodate treatment of native antigens revealed that responses to the two secreted preparations were overwhelmingly directed against glycans rather than peptides. Considerable immunological cross-reactivity between glycans in the two preparations was inferred from a comparison of sera from infected-only and vaccinated-only animals, predominantly exposed to egg and cercarial secretions, respectively. In contrast, when somatic antigen preparations derived from adult worms or eggs were used to probe sera, a stronger antipeptide response was seen that accounted for up to 66% of maximum reactivity. Probing of sera with defined glycan structures confirmed the time course of responses and the presence of cross-reactive epitopes. In spite of the intense antiglycan response elicited in mice by administration of live eggs, no protection against a cercarial challenge was observed. Our data further support the hypothesis that antiglycan responses are a smokescreen with negligible protective potential.