IL-4 and IL-13, two related Th2-type cytokines, play critical and redundant roles in the defense against gastrointestinal nematodes. These cytokines exert various immunological and physiological effects to expel these worms; however, it had not been known whether protease/protease inhibitor interaction was involved in the defense mechanism against these parasites. Many protozoan and helminth parasites generate cysteine proteases, the majority of which are orthlogues of mammalian cathepsin L, and these cysteine proteases play key roles in the life cycle of parasites as they infect and/or adapt to the hosts. We previously found that the squamous cell carcinoma antigens (SCCA1) and SCCA2, members of the ovalbumin serpin family, were secreted from epithelial cells upon stimulation by IL-4 or IL-13. SCCA1 and SCCA2 show different inhibitory profiles. We recently found that SCCA1, but not SCCA2, inhibited several parasitederived cysteine proteases. Furthermore, SCCA molecules employed a unique inhibitory mechanism against cysteine proteases: they interacted with proteases without forming a covalent complex followed by irreversible impairment of the protease activities and they resisted cleavage by the target proteases. These results indicate that the interaction between cysteine proteases of parasites and SCCA molecules may be a novel immunodefense mechanism of Th2-type responses against parasites, particularly helminths. In this article, we summarize the roles of IL-4/IL-13 on the defense mechanism against parasites, the effects of SCCA molecules against extrinsic cysteine proteases, and the correlation between induction of SCCA molecules and allergic diseases.