Death receptor mediated apoptosis of hepatocytes contributes to hepatitis and fulminant liver failure. microRNAs (miRNAs), 19-25 nucleotide-long noncoding RNAs, have been implicated in the post-transcriptional regulation of the various apoptotic pathways. Here we report that global loss of miRNAs in hepatic cells leads to increased cell death in a model of FAS/CD95 receptor induced apoptosis. miRNA profiling of murine liver identified 11 conserved miRNAs, which were upregulated in response to FAS induced fulminant liver failure. We show that ectopic expression of miR-221, one of the highly upregulated miRNAs in response to apoptosis, protects primary hepatocytes and hepatoma cells from apoptosis. Importantly, in vivo overexpression of miR-221 by adeno-associated virus serotype 8 (AAV8) delays FAS induced fulminant liver failure in mice. We additionally demonstrate that miR-221 regulates hepatic expression of Puma, a well-known pro-apoptotic member of the Bcl2 protein family. In conclusion, we identified miR-221 as a potent post-transcriptional regulator of FAS induced apoptosis. miR-221 may serve as a potential therapeutic target for the treatment of hepatitis and liver failure.