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We show that chymotrypsin-like, as well as trypsin-like, proteases are in granules isolated from cytolytic lymphocytes by the capacity of the granules to hydrolyze the peptide substrates Z-Phe-Leu-Phe-SBzl and Z-Ala-Gly-Arg-SBzl, respectively. We report protease inhibitors that can abrogate or delay granule-mediated cytolysis. Two mechanism-based isocoumarin serine protease inhibitors and Z-Gly-Leu-Phe-CH2Cl completely abrogated granule cytolysis. Lima bean and soybean trypsin inhibitors and chymostatin delayed but did not prevent this cytolysis. These data represent the first use of the powerful isocoumarin inhibitors as biological probes and indicate that lymphocyte serine proteases participate in the granule cytolytic process.