One of the important posttranslational protein modifications is histone acetylation or deacetylation. Acetylation is catalyzed by the dedicated histone acetyltransferases and has been generally considered to be associated with transcription activation, while deacetylation is catalyzed by histone deacetylases (HDACs). One of the classes of HDACs called sirtuins are NAD+-dependent deacetylases. There are seven sirtuins in mammals from Sirt1 - Sirt7. In this work, we study Sirt6, one of the sirtuins reported to have a weak deacetylase activity in vitro. However, Sirt6 has been involved in various important biological functions like life span expansion, genomic stability, transcriptional regulation, and metabolism. At the biochemical level, Sirt6 deacetylation has been attributed to most of these biological functions. We found that human sirtuin Sirt6 can remove longer chain fattyacyl groups, such as myristoyl group, on the lysine residue much more efficiently than acetyl group. It is shown that this novel activity of Sirt6 allows it to accommodate more substrates other than H3K9. The catalytic efficiency for this new defattyacylase activity was found to be comparable to sirtuins with robust deacetylase activity. Further, the physiological relevance of this activity shows that Sirt6 promotes the secretion of TNF[alpha] by defattyacylating it at K19/K20 lysine residue.