The adaptive radiation of African cichlids is a prime model system for studying vertebrate speciation. Cichlid species are distributed in lakes and rivers with various water conditions such as various pH values. The innate immune system in fish is particularly important because water contains a wide range of pathogenic microorganisms. To investigate the evolution of the host defense system in cichlids, we isolated the c-type lysozyme gene, which functions in the innate immune system of fish. Southern blot and sequence analyses showed that the lysozyme gene underwent several gene duplication events and evolved with amino acid replacements during the adaptive radiation of cichlids. The inferred 3D structure revealed that the amino acid substitutions were localized on the lysozyme surface. Moreover, more than half of the surface substitutions changed the charge of amino acid residues, suggesting changes in the optimum pH for enzymatic activity. In African cichlids, the lysozyme genes may have played and still play an important role in defense against pathogens.