AbstractStabilization of a protein using cavity‐filling strategy has hardly been successful because of unfavorable van der Waals contacts. We succeeded in stabilizing lysozymes by cavity‐filling mutations. The mutations were checked by a simple energy minimization in advance. It was shown clearly that the sum of free energy change caused by the hydrophobicity and the cavity size was correlated very well with protein stability. We also considered the aromatic–aromatic interaction. It is reconfirmed that the cavity‐filling mutation in a hydrophobic core is a very useful method to stabilize a protein when the mutation candidate is selected carefully.