The C19MC gene on chromosome band 19q13.4 encodes a cluster of 46 microRNAs; those microRNAs are normally only expressed from the paternal allele and in the placenta. Placental expression correlates with selective demethylation of the paternal C19MC promoter, in contrast to methylation of both maternal and paternal alleles in nonplacental tissues. Prior investigations demonstrated “ectopic” activation of this gene in most hepatic mesenchymal hamartomas, including sporadic tumors and others with androgenetic-biparental mosaicism (subset of cells are diploid, but contain only paternally derived chromosomes). In the present investigation of C19MC promoter methylation status in a series of 14 mesenchymal hamartomas, a demethylated allele was identified in 6 tumors, including all 4 with androgenetic-biparental mosaicism. Conversely, only methylated alleles were cloned from sporadic hamartomas, including 3 tumors with chromosomal rearrangements thought likely to activate C19MC expression independent of the native promoter. In conjunction with published data, the findings suggest multiple molecular mechanisms for C19MC activation in hepatic mesenchymal hamartoma, including the existence of a normal placental imprinting pattern in mesenchymal cells in a subset of cases. Some or all of the latter hamartomas may result from placental “grafting,” a hypothesis supported by endothelial expression of the placental vascular marker, glucose transporter-1, in 1 of the 6 cases with a demethylated allele.