Mutations Arg117→His and Asn21→Ile of the human cationic trypsinogen have been recently identified in patients affected by hereditary pancreatitis (HP). The Arg117→His substitution is believed to cause pancreatitis by eliminating an essential autolytic cleavage site in trypsin, thereby rendering the protease resistant to inactivation through autolysis. Here we demonstrate that the Arg117→His mutation also significantly inhibits autocatalytic trypsinogen breakdown under Ca²⁺-free conditions and stabilizes the zymogen form of rat trypsin. Taken together with recent findings demonstrating that the Asn21→Ile mutation stabilizes rat trypsinogen against autoactivation and consequent autocatalytic degradation, the observations suggest a unifying molecular pathomechanism for HP in which zymogen stabilization plays a central role.