High molecular weight kininogen has been shown to be the principal plasma inhibitor of cellular thiol proteases including cathepsins B, H and L and calpains 1 and 2. Since these same enzymes have been reported to be elevated in animals with muscular dystrophy, we studied plasmas from hamsters with muscular dystrophy and compared these to normal hamster plasma. The ability of plasma to inhibit purified platelet calpain was assayed and found to be 62% of normal. Since low molecular weight kininogen can also inhibit calpain, the coagulant activity of kininogen, an activity unique for high molecular weight kininogen, was determined in dystrophic hamster plasma and found to be 69% of normal in close agreement with the calpain inhibitory activity. The contribution of the other plasma calpain inhibitor alpha 2-macroglobulin appeared small since inactivation with methylamine did not alter the ability to inhibit calpain in either normal or dystrophic plasma. We conclude that there is a selective deficiency of plasma high molecular weight kininogen in dystrophic hamsters, an abnormality which could play a role in the pathogenesis of this disorder.