Sirtuins really are a type of enzymes initially recognized as nicotinamide adenine dinucleotide (NAD)-dependent protein lysine deacetylases. One of the seven mammalian sirtuins, SIRT1-7, only SIRT1-3 possess efficient deacetylase activity in vitro, whereas SIRT4-7 possess very weak in vitro deacetylase activity. Several sirtuins that exhibit weak deacetylase activity have lately been proven to own more effective activity for that removal other acyl lysine modifications, for example succinyl lysine and palmitoyl lysine. Here, we show the well-known deacetylase SIRT2 offers efficient activity for removing lengthy-chain fatty acyl groups. The catalytic efficiency (kcat/Km) for removing a myristoyl group is slightly greater than that for removing an acetyl group. The very structure of SIRT2 in complex having a thiomyristoyl peptide reveals that SIRT2 offers a sizable hydrophobic pocket that may accommodate the myristoyl group. Comparison from the SIRT2 acyl pocket to individuals of SIRT1, SIRT3, and SIRT6 reveals the acyl pockets of SIRT1-3 are highly similar, and also to a smaller degree, much like those of SIRT6. The efficient in vitro demyristoylase activity of SIRT2 shows that this activity might be physiologically relevant and warrants future investigative studies.