Since metalloenzymes are a large collection of metal ion(s) dependent enzymes, comparison analyses of metalloenzyme active sites are critical for metalloenzyme de novo design, function investigation, and inhibitor development. Here, we report a method named MeCOM for comparing metalloenzyme active sites. It is characterized by metal ion(s) centric active site recognition and three-dimensional superimposition using α-carbon or pharmacophore features. The test results revealed that for the given metalloenzymes, MeCOM could effectively recognize the active sites, extract active site features, and superimpose the active sites; it also could correctly identify similar active sites, differentiate dissimilar active sites, and evaluate the similarity degree. Moreover, MeCOM showed potential to establish new associations between structurally distinct metalloenzymes by active site comparison. MeCOM is freely available at https://mecom.ddtmlab.org.