Uterine serous carcinomas (USCs) and poorly differentiated (International Federation of Gynecology and Obstetrics Grade 3) endometrioid adenocarcinomas (ECs) are two histologic subtypes of high-grade uterine carcinoma that differ in clinical presentation, patterns of dissemination, and biologic aggressiveness. To investigate the mechanisms responsible for this heterogeneity, we studied CD44 and CD44v6 expression in a series of 20 USCs and 21 poorly differentiated ECs. CD44 is a protein involved in cell adhesion and lymphocyte homing, and one of its isoforms, CD44v6, might be related to capillary-lymphatic space invasion and metastasis. Eight (40%) of 20 USCs expressed CD44, compared with 18 (86%) of 21 ECs (P < .005). None of the USCs were reactive with antibodies against CD44v6, whereas 45% of the ECs were immunoreactive (P < .001). CD44v6 expression was observed in the myoinvasive ECs but was not seen in foci of capillary-lymphatic space invasion in either the ECs or the USCs. In summary, the USCs were significantly more likely to demonstrate a CD44- and CD44v6-negative phenotype than were the poorly differentiated ECs.