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Intrahepatic cholangiocarcinoma is a treatment refractory malignancy with a high mortality and an increasing incidence worldwide. Recent studies have observed that activation of Notch and AKT signaling within mature hepatocytes is able to induce the formation of tumors displaying biliary lineage markers, thereby raising the suggestion that it is hepatocytes, rather than cholangiocytes or hepatic progenitor cells that represent the cell of origin of this tumor. Here, we use a cholangiocyte-lineage tracing system to target p53 loss to biliary epithelia and observe the appearance of labeled biliary lineage tumors in response to chronic injury. Consequent to this, upregulation of native functional Notch signaling is observed to occur spontaneously within cholangiocytes and hepatocytes in this model as well as in human intrahepatic cholangiocarcinoma. These data prove that in the context of chronic inflammation and p53 loss, frequent occurrences in human disease, biliary epithelia are a target of transformation and an origin of intrahepatic cholangiocarcinoma. Cancer Res; 74(4); 1-6. ©2013 AACR.