We report the first comprehensive study of a case of metastatic mixed fibrolamellar hepatocellular carcinoma (mFL-HCC) by exome and transcriptome sequencing. We found no evidence for HBV or HCV expression or genome integration,TERTpromoter mutations or other common HCC-associated mutations. The very low mutation rate of this case, large number of mostly single-copy, long-range copy number variant events, and high expression ofERBB2were more consistent with previous reports of pure FL-HCC than conventional HCC. In particular, a recently discovered fusion transcript specifically associated with pure FL-HCC and involvingDNAJB1andPRKACAwas detected at very high expression levels. Subsequent analysis of the primary tumor and additional metastases revealed the presence of this fusion in all assayed samples, including samples with mixed or conventional HCC pathology. A novel BAC-capture approach was developed to allow identification of a 400kb deletion as the underlying genomic mechanism for the fusion. A second case of mFL-HCC confirmed our finding that theDNAJB1:PRKACAfusion was detectable in conventional components. Finally, we used sensitive detection methods to screen an additional 112 HCC and 44 adjacent non-tumor liver samples for this fusion and identified a single case of HCC, which upon review, also had both conventional and fibrolamellar features. These results indicate that theDNAJB1:PRKACAfusion can be used as a diagnostic tool for both pure and mFL-HCC.