Serous carcinoma of the ovary has been traditionally graded as well-differentiated, moderately differentiated, and poorly differentiated (ie, a 3-tier system). A new 2-tier system grades serous carcinomas into low or high grade. Recent morphologic and molecular studies have shown that invasive well-differentiated serous carcinoma, referred to by us as "invasive low-grade micropapillary serous carcinoma," is clearly distinct from high-grade serous carcinoma from the standpoint of pathogenesis and clinicopathologic features. As high-grade serous carcinoma is histologically heterogeneous, the goal of this study was to determine, based on molecular and drug resistance data, whether further subclassification of high-grade serous carcinomas into additional grades (moderately and poorly differentiated) has biologic validity. One hundred eleven ovarian and peritoneal high-grade serous carcinomas further subclassified as moderately and poorly differentiated types using the International Federation of Gynecology and Obstetrics (FIGO) grading system were analyzed for TP53 mutations and in vitro extreme drug resistance to 10 chemotherapeutic drugs. Seventy-six and 35 cases were subclassified as moderately and poorly differentiated, respectively. A TP53 mutation was present in 84% of moderately and 70% of poorly differentiated types of high-grade serous carcinomas, respectively (P=0.21), and there were no significant differences in the frequency of extreme drug resistance for each of the 10 drugs tested (P values ranging from 0.14 to >0.99). Although additional investigation is warranted, this study suggests that subclassification of high-grade serous carcinoma into moderately and poorly differentiated is not relevant. Accordingly, they can be simply classified as high-grade serous carcinoma.