Restriction endonucleases are well known because of their use in genetic engineering. However, many groups of these enzymes that are not suitable for practical use have been studied much worse. Type III restriction endonucleases are among the least studied major groups of these enzymes. In particular, such endonucleases are poorly represented in protein domain databases, which can be explained by the large size of these proteins and their complex domain organization, including regions of unidentified spatial structure and highly variable sequence. In this work we used predicted structures of Type III restriction endonucleases to detect the catalytic domains that perform hydrolysis of DNA. As a result, seven families of such domains were identified and described with HMM profiles. The obtained profiles were used to classify all known Type III restriction endonucleases, correct their annotations, and search for new representatives in complete prokaryotic genomes.