The proteolytic actjvity of papain was investigated with respect to its action on both natural substrates (native papaya protein and bovine serum albumin) and artificial synthetic substrate (benzoyl~l-arginine ethyl ester). Following removal of 30 percent and 40 percent of the amino acid residues from the amine terminus, the activity of the degraded papain was determined with respect to the above substrates, and compared to the activity of the intact papain molecule. Native papaya protein showed resistance to digestion by both intact papain and 30 percent 'degraded papain. This resistance to digestion persisted for time periods ranging from three to six hours and was not found with the other substrates. Papaya protein did not show this resistance to digestion by 40 percent degraded papain. Digestion began immediately upon addition of 40 percent degraded papain to papaya protein. In contrast to this, papaya protein showed no resistance to digestion by other proteolytic enzymes, both of plant and animal origin. These investigations clearly showed an interaction between native papaya protein and papain, which serves to prevent digestion of the native papaya protein by papain. This interaction was shown to be with a region of the papain between amtno acid residue 62 (30 percent degraded papain) and amino acid residue 84 (40 percent degraded papain). It is suggested that this type of interaction may be a general mechanism for the prevention of digestion of native proteins by the enzymes of the host. If this is the case, then the papain-papaya protein system could serve as an easily controlled model system for the investigation of other such enzyme systems.