We compared proteolysis of H2O2/hemin-cross-linked myosin and the native protein. Pepsin, trypsin, and chymotrypsin, representative enzymes of the mammalian digestive tract, and the plant enzyme papain were chosen as proteases. Under conditions which caused prominent degradation of the native myosin, only minimal degradation of the cross-linked protein was observed when individual enzymes were applied. Successive proteolysis by pepsin at gastric pH (1.85) followed by trypsin and chymotrypsin at duodenal pH (8.0) also showed retarded proteolysis of cross-linked myosin. At low pH both myosin forms precipitated, but by elevation of the pH only cross-linked myosin was partially resolubilized and the solubility was augmented following its minimal proteolytic degradation. It was concluded that although in general oxidatively modified proteins are susceptible to proteolysis, oxidatively cross-linked myosin is resistant. The data suggest that decreased digestibility of cross-linked myosin may lead to reduced quality of oxidized muscle foods.