We present a comparative analysis of sex-specific tegument proteins of paired or virgin Schistosoma mansoni. By apply a new and highly sensitive workflow, detection of even low abundance proteins from the worm was achieved Therefore, a streptavidin-biotin affinity purification technique in combination with single pot solid-phase enhanced sample preparation was established for subsequent LC-MS/MS analysis. We were able to identify 1519 tegument proteins for male and female as to virgin and paired worms. Sex-specific proteins were screened, present in both virgin and paired adult schistosomes to reduce the impact of mating. Bioinformatic analysis revealed an involvement of female-specific tegument proteins in signaling pathways of cellular processes and antioxidant mechanisms. Male-specific proteins were found to be enriched in processes linked to phosphorylation and signal transduction. This suggests a task sharing between the sexes that might be necessary for survival in the host. Our datasets provide a basis for further studies to understand and ultimately decipher the strategies of the two worm sexes to evade the immune system.