Background Endometrial carcinoma (EC) and serous ovarian carcinoma (OvCa) are both among the common cancer types in women. EC can be divided into two subtypes, endometroid EC and serous-like EC, with distinct histological characterizations and molecular phenotypes. There is an increasing awareness that serous-like EC resembles serous OvCa in genetic landscape, but a clear relationship between them is still lacking. Methods Here, we took advantage of the large-scale molecular profiling of The Cancer Genome Atlas(TCGA) to compare the two EC subtypes and serous OvCa. We used bioinformatics data analytic methods to systematically examine the somatic mutation (SM) and copy number alteration (SCNA), gene expression, pathway activities, survival gene signatures and immune infiltration. Based on these quantifiable molecular characterizations, we asked whether serous-like EC should be grouped more closely to serous OvCa, based on the context of being serous-like; or if should be grouped more closely to endometroid EC, based on the same organ origin. Results We found that although serous-like EC and serous OvCa share some common genotypes, including mutation and copy number alteration, they differ in molecular phenotypes such as gene expression and signaling pathway activity. Moreover, no shared prognostic gene signature was found, indicating that they use unique genes governing tumor progression. Finally, although the endometrioid EC and serous OvCa are both highly immune infiltrated, the immune cell composition in serous OvCa is mostly immune suppressive, whereas endometrioid EC has a higher level of cytotoxic immune cells. Overall, our genetic aberration and molecular phenotype characterizations indicated that serous-like EC and serous OvCa cannot be simply treated as a simple “serous” cancer type. In particular, additional attention should be paid to their unique gene activities and tumor microenvironments for novel targeted therapy development.