Benign or malignant mural nodules rarely occur in mucinous tumors (MTs) of the ovary and malignant nodules can show mesenchymal or epithelial differentiation. The histogenesis of mural nodules is unclear and it has been suggested that these may evolve through divergent differentiation of the mucinous neoplasm or alternatively represent a collision phenomenon. To test these possibilities we compared the molecular profile of 7 ovarian MTs with their matched mural carcinomatous nodules (MCNs) by next-generation sequencing. We found identical KRAS mutations in paired MTs and MCNs in 6 cases, one of which also showed identical CDH1 mutations in both components. In 1 tumor a KRAS mutation was detected in the mucinous neoplasm but not in the MCN; however, identical p53 mutations were present in both tumor elements. Unpaired p53 and PTEN mutations were detected only in the MCN in 2 cases, while mutations in p53 and PIK3CA genes were observed only in the MT in 2 cases. The overall comparative genomic profile was consistent with the neoplastic nature of the MCNs and strongly supported their clonal relationship with the more differentiated mucinous neoplasms. MCNs possibly develop through the acquisition of additional genomic alterations, such as p53 and PTEN mutations, resulting in an anaplastic morphologic phenotype. Our findings also suggest that ovarian MTs with MCNs often arise in KRAS mutant neoplasms. However, mutations in other genes such as PIK3CA and CDH1 may play a role in the neoplastic evolution of a subset of these tumors.