Comparison of the amino acid sequences of nine different pyridoxal-5′-phosphate-dependent amino acid decarboxylases indicated that they can be subdivided into four different groups that seem to be evolutionarily unrelated to each other. Group I is represented by glycine decarboxylase, a component of a multienzyme system; group II comprises glutamate, histidine, tyrosine, and aromatic-l-amino-acid decarboxylases; group III, procaryotic ornithine and lysine decarboxylase as well as the procaryotic biodegradative type of arginine decarboxylase; group IV, eucaryotic ornithine and arginine decarboxylase as well as the procaryotic biosynthetic type of arginine decarboxylase and diaminopimelate decarboxylase. (N–1) profile analysis, a more stringent application of profile analysis, established the homology among the enzymes of each group. A search with the profile of group II indicated a distant relationship with aminotransferases and thus with the α family of pyridoxal-5′-phosphate-dependent enzymes. No evidence was obtained that groups I, III and IV were related with other pyridoxal-5′-phosphate-dependent enzymes or any other protein in the databse. Unlike the aminotransferases, which, with few possible exceptions, costitute a single group of homologous proteins, the amino acid decarboxylases, by the criterion of profile analysis, have evolved along multiple lineages, in some cases even if they have the same substrate specificity.