We report the case of an 84-year-old man with asymptomatic chronic hepatitis C virus (HCV) infection treated with direct antiviral agents. At the end of the antiviral therapy laboratory tests showed an abrupt increase in cholestasis parameters and aminotransferases, associated with anti-mitochondria antibodies positivity. Therefore, primary biliary cholangitis (PBC) was diagnosed. The patient was treated with ursodeoxycholic acid achieving a good biochemical response. This is the second case described in literature of PBC onset after HCV eradication with an interferon-free antiviral regimen. In both cases an autoimmune damage of cholangiocytes secondary to the immunological derangement caused by virus clearance may be hypothesized. Indeed, according to the hygiene hypothesis, when two different triggers act simultaneously on the immune system they tend to be mutually inhibitory, and an immune tolerance develops; when one of these triggers disappears (as HCV in this case), the immune system may mount a response against self-antigens, causing autoimmune disorders such as PBC.