Aspartic (AP) and cysteine proteinase (CP) activities were shown to be present in soluble extracts of adult Schistosoma japonicum and S. mansoni. Both activities degraded human hemoglobin. However, the respective proportions of these activities differed between the species and S. mansoni, but not S. japonicum, contained a third minor hemoglobinolytic activity. These differences between the species were valid for both sexes. When cyclosporin A (CsA) was administered to infected mice and schistosomes were recovered by perfusion 4 days later, the AP and CP activities were inhibited in female worm extracts of both species. Male activities were, however, either unaffected or markedly enhanced. This sex-dependent in vivo effect of CsA was confirmed for the CP activity (including schistosome cathepsin B) using fluorogenic peptidyl substrates. In contrast, when CsA was added directly to extracts of normal worms in vitro, CP activity was enhanced and this effect was independent of worm sex. This study identifies specific proteinases which are susceptible to in vivo modulation by CsA. It also demonstrates that this drug may stimulate proteinase activity in vitro. The results are discussed with reference to the drug's possible mechanism(s) of action.