Increasingly, high-grade serous carcinomas (HGSCs) of fallopian tube/ovarian origin are managed initially with neoadjuvant chemotherapy (NACT) and pre-treatment diagnosis is often based upon relatively limited core biopsy and/or cytology specimens. Endometrial HGSC can also present with adnexal and peritoneal metastasis, thus mimicking a primary tubo-ovarian neoplasm, but the role of NACT in these cases is less established. Immunohistochemistry has been considered useful in this distinction but with a wide range of reported findings in the literature. In this study we have examined tumour growth patterns and the expression p16, Ki-67, WT1, PAX2, HER2, ER-α, ER-β, PR, and BAF250a in 18 tubo-ovarian and 14 endometrial HGSCs, comparing the findings in primary and omental sites. Metastatic tubo-ovarian carcinomas demonstrated significantly more varied architectural patterns than metastatic endometrial HGSCs (median 2.5 versus 1). None of the immunohistochemical markers proved completely reliable but only endometrial HGSC were WT1 negative (7/14 metastatic tumours) or demonstrated over-expression of HER2 (2/14 cases). Micropapillary tumour elements more often showed retained PAX2 and WT1 expression, low Ki-67 labelling, and (in endometrial tumours) PR staining. Diverse architectural patterns suggest tubo-ovarian origin in a metastatic HGSC. Immunohistochemical results should be cautiously interpreted, particularly in small specimens.