Purpose <p>Grade 3 endometrial carcinoma (Gr3 Ca) is a diverse group of tumors that vary in their pathogenesis and clinical behavior. Their morphology and immunohistochemical (IHC) profile demonstrate a significant overlap, posing a considerable challenge in differentiating between Grade 3 endometrioid and serous carcinoma. The present study aims to assess the effectiveness of a limited IHC panel in distinguishing the two entities.</p> Methods <p>A retrospective study comprising morphologically defined 39 cases of grade 3 endometrial carcinoma (22 serous and 17 grade 3 endometrioid) was studied for clinicopathological factors and evaluated with an immunohistochemical panel of ER, PR, p53, and p16.</p> Results <p>There was a significant difference in age at presentation(<i>p</i> = 0.02), lymphovascular invasion(<i>p</i> = 0.04), and locoregional spread(<i>p</i> = 0.05) between the two groups of tumors. ER and PR expressions were more common and diffuse in Gr3 Ca than serous, but only the difference in expression of PR was statistically significant. Aberrant expression of p53(95%) and diffuse expression of p16(91%) were almost ubiquitous in serous carcinoma which was less frequent in Gr3 Ca (<i>p</i> = 0.001 and <i>p</i> = 0.002 respectively). Aberrant expression of p53 and absence of PR were predictive of serous histology. MMRd was noted in 12% of Gr3 Ca cases and 65% cases grouped as high risk of recurrence based on IHC panel.</p> Conclusion <p>Endometrial serous carcinomas are more aggressive tumors and an IHC panel of ER, PR, p53, and p16 is useful in distinguishing it from grade 3 endometrioid carcinoma. Absence or decreased expression of PR coupled with aberrant expression of p53 is predictive of serous histology.</p>